MXPA03008888A - Inhibitors of c-jun n-terminal kinases (jnk) and other protein kinases. - Google Patents

Inhibitors of c-jun n-terminal kinases (jnk) and other protein kinases.

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MXPA03008888A
MXPA03008888A MXPA03008888A MXPA03008888A MXPA03008888A MX PA03008888 A MXPA03008888 A MX PA03008888A MX PA03008888 A MXPA03008888 A MX PA03008888A MX PA03008888 A MXPA03008888 A MX PA03008888A MX PA03008888 A MXPA03008888 A MX PA03008888A
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disease
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MXPA03008888A
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Nanthakumar Susanthini
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Vertex Pharma
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Abstract

The present invention provide a compound of formula I or II:or a pharmaceutically acceptable derivative thereof, wherein R1, R2, R3, and R4 are as described in the specification. These compounds are inhibitors of protein kinase, particularly inhibitors of JNK, a mammalian proteinkinase involved cell proliferation, cell death and response to extracellular stimuli; and Src-family kinases, especially Src and Lck kinases. These compounds are also inhibitors of GSK3 and CDK2 kinases. The invention also relates to methods for producing these inhibitors. The invention also provides pharmaceutical compositions comprising the inhibitors of the invention and methods of utilizing those compositions in the treatment and prevention of various disorders.

Description

INHIBITORS OF N-TERMINAL C-JUN CINASAS (JNK) AND OTHER PROTEIN CINACAS CROSS REFERENCE WITH RELATED REQUESTS This application claims the priority of the Provisional Patent Application 60 / 279,961 filed on March 29, 2001, the content of which is incorporated herein by reference.
FIELD OF THE INVENTION The present invention relates to inhibitors of protein kinase, especially to N-terminal c-Jun kinases (JNK) and the Src family of kinases, which are members of the protein kinase family activated by the mitogen (MA.P). There are several different genes and isoforms that code for JNK. Members of the JNK family regulate signal transduction in response to environmental stress and proinflammatory cytokines and are involved in the mediation of several different disorders. In several diseases of the human being members of the Src family are involved. The invention also relates to inhibitors of the GSK3 kinase which is involved in the disease of diabetes and in other disorders and to the CDK2 kinase which plays a role in the regulation of the cell division cycle. The P03 / 12S-VPI invention also provides pharmaceutical compositions containing the inhibitors of the invention and methods for using those compositions in the treatment and prevention of different disorders.
BACKGROUND OF THE INVENTION Mammalian cells respond to extracellular stimulation by activating signaling cascades that are mediated by members of the family of mitogen-activated protein kinase (MAP), which include kinases regulated by the extracellular signal (ERKs), MAP kinases p38 and N-terminal c-Jun kinases (JNKs). MAP kinases (MAPKs) are activated by a variety of signals including growth factors, cytokines, UV radiation and stress-inducing agents. MAPKs are serine / threonine kinases and their activation occurs by the dual phosphorylation of threonine and tyrosine in the Thr-X-Tyr segment in the activation loop. MAPKs perform phosphorylation on different substrates that include transcription factors, which in turn regulate the expression of specific sets of genes and thus mediate a specific response to the stimulus. In the c-Jun N-terminal protein kinases, also known as JNKs, three distinct genes have been identified, JNK1, JNK2, JNK3 and there are at least ten P03 / 125-VPI different splicing isoforms of JNKs in mammalian cells [Gupta et al., EMBO J., 15: 2760-70 (1996)]. Members of the JNK family are activated by proinflammatory cytokines, such as tumor necrosis factor-a (TNFa) and interleukin-1β (IL-? ß), as well as by environmental stress, which includes anisomycin, UV irradiation , hypoxia and an osmotic shock [Minden et al., Biochemistry et Biophysica Acta, 1333: F85-F104 (1997)]. The 3 'substrates of the JNKs include transcription factors c-Jun, ATF-2, Elkl, p53 and a cell death domain protein (DENN) [Zhang et al. Proc. Nati Acad. Sci. USA, 95: 2586-91 (1998)]. Each JNK isoform binds to these substrates with different affinities, suggesting a regulation of signaling pathways by the substrate specificity of different JNKs in vivo (Gupta et al., Supra). JNKs, along with other MAPKs, have been implicated in having a role in the cellular mediation response to cancer, platelet aggregation induced by thrombin, immunodeficiency disorders, autoimmune diseases, cell death, allergies, osteoporosis and heart disease. The therapeutic conditions related to the activation of the trajectory of JNK include chronic myelogenous leukemia (CML), rheumatoid arthritis, asthma, osteoarthritis, ischemia, cancer and diseases.
P03 / 125-VPI neurodegenerative. Different reports detail the importance of JNK activation associated with liver disease or episodes of hepatic ischemia [Nat. Genet 21: 326-9 (1999); FEBS Lett. 420: 201-4 (1997); J. Clin. Inves. 102: 1942-50 (1998); Hepatology 28: 1022-30 (1998)]. A role of JNK in cardiovascular disease such as myocardial infarction or congestive failure in the heart has been reported to have shown that JNK mediates hypertrophic responses in different forms of cardiac stress [Circ. Res. 83: 167-78 (1998); Circulation 97: 1731-7 (1998); J. Biol. Chem. 272: 28050-6 (1997); Circ. Res. 79: 162-73 (1996); Circ. Res. 78: 947-53 (1996); J. Clin. Invest. 97: 508-14 (1996)]. It has been shown that the JNK cascade also plays a role in the activation of the T cell, including the activation of the IL-2 promoter. In this way, the JNK inhibitors can have a therapeutic value in the alternating pathological immune responses [J. Immunol. 162: 3176-87 (1999); Eur. J. Immunol. 28: 3867-77 (1998); J.
Exp. Med. 186: 941-53 (1997); Eur. J. Immunol. 26: 989-94 (1996)]. A role for the activation of JNK in different cancers has also been established, which suggests the potential use of JNK inhibitors in cancer.
P03 / 125-VPI For example, a constitutively activated JNK is associated with tumorigenesis mediated by HTLV-1 [Oncogene 13: 135-42 (1996)]. The proliferative effects of bFGF and OSM have a role on Kaposi sarcoma cells (S) are mediated by their activation of the pathway of JNK signaling [J. Clin. Invest. 99: 1798-804 (1997)]. Other proliferative effects of other cytokines involved in the proliferation of KS, such as vascular endothelial growth factor (VEGF), IL-6 and TNF'oc, can also be mediated by JNK. In addition, the regulation of the c-jun gene in the transformed BCR-ABL p210 cells corresponds to the activity of the JNK, which suggests a role for the JNK inhibitors in the treatment for chronic myelogenous leukemia (CML) [Blood 92: 2450-60 (1998)]. JNK1 and JNK2 are widely expressed in a variety of tissues. In contrast, JNK3 is selectively expressed in the brain and to a lesser extent in the heart and testes [Gupta et al., Supra; Mohit et al., Neuron 14: 67-78 (1995); Martin et al., Brain Res. Mol. Brain Res. 35: 47-57 (1996)]. JNK3 has been linked to neuronal apoptosis induced by kainic acid, which indicates a role for JNK in the pathogenesis of glutamate neurotoxicity. In the adult human brain, the expression of JNK3 is located in a subpopulation of the pyramidal neurons CAI, CA4 and in the subiculum regions P03 / 125-VPI of the hippocampus and layers 3 and 5 of the neocortex [Mohit et al. , supra]. The CAI neurons of patients with acute hypoxia show strong nuclear immunoreactivity of the LTNK3 compared to the cytoplasmic, minimal diffuse staining of the hippocampal neurons of the brain tissues of normal patients [Zhang et al., Supra]. In this way, JNK3 seems to be involved in the hypoxic and ischemic damage of the CAI neurons in the hippocampus. In addition, UTNTK3 is co-localized immunochemically with vulnerable neurons in Alzheimer's disease [Mohit et al., Supra]. The discontinuity of the JNK3 gene caused by the resistance of the mice to the kainic acid agonist of the excitotoxic glutamate receptor, which includes the effects on seizure activity, AP-1 transcriptional activity and apoptosis of hippocampal neurons, indicating that the trajectory The signaling of J K3 is a crucial component in the pathogenesis of glutamate neurotoxicity [Yang et al., Nature, 389: 865-870 (1997)]. Based on these findings, the JNK signaling, especially that of J K3, has been implicated in areas such as neurodegenerative diseases driven by apoptosis, such as Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis (ALS), epilepsy and seizures, Huntington's disease, P03 / 125-VPI traumatic injuries in the brain, as well as ischemic stroke and hemorrhagic stroke. There is a great unmet medical need to develop specific inhibitors of JNK that are useful to treat the different conditions associated with JK activation., especially considering the relatively inadequate treatment options that are now available for most of these conditions. The Src family of kinases are involved in cancer, immune system dysfunction and diseases that reshape bones. For a general review, see Thomas and Brugge, Annu. Rev. Cell Dev. Biol. (1997) 13, 513, Lawrence and Niu, Pharmacol. Ther. (1998) 77, 81, Tatosyan and Mizenina, Biochemistry (Moscow) (2000) 65, 49, Boschelli et al., Drugs of the Future 2000, 25 (7), 717, (2000). Members of the Src family include the following eight kinases in mammals: Src, Fyn, Yes, Fgr, Lyn, Hck, Lck, Blk, and Yrc. These are non-receptor protein kinases that vary in molecular mass from 52 to 62 kD. All are characterized by a common structural organization that is constituted by six different functional domains: homology domain 4 (SH4), a single domain, SH3 domain, SH2 domain, a catalytic domain (SH1) and a C-terminal regulatory region. Tatosyan et al.
P03 / 125-VPI Biochemistry- (Moscow) 65, 49-58 (2000). Based on the published studies, Src kinases are considered as potential therapeutic targets for different human diseases. Mice suffering from Src deficiency develop osteoporosis or an increase in bones, due to the non-pressure resorption of the bones by osteoclasts. This suggests that osteoporosis resulting from the abnormally high bone resorption can be treated by inhibiting Src 'Soriano et al., Cell, 69, 551 (1992) and Soriano et al., Cell, 64, 693 (1991). The suppression of arthritic destruction of bones by overexpression of CSK in synoviocytes and osteoclasts has been achieved. Takayanagi et al., J. Clin. Invest., 104, 137 (1999). CSK or the C-terminal Src kinase, performs phosphorylation and thereby inhibits the catalytic activity of Src. This implies that the inhibition of Src can prevent the destruction of the joints that is characteristic in patients suffering from rheumatoid arthritis. Boschelli et al., Drugs of the Future 2000, 25, (7), 717, (2000). Src also plays a role in the replication of the hepatitis B virus. The virally encoded transcription factor HBx activates Src in a step required for the propagation of the virus. Klein et al., EMBO J., 18, P03 / 125-VPI 5019, (1999) and Klein et al., Mol. Cell. Biol., 17, 6427 (1997). Several studies have linked the expression of Src with cancer of the colon, liver and pancreatic cancer type, certain leukemias and lymphoblasts of the B cell. Talamonti et al., J. Clin. Invest., 91, 53 (1993), Lutz et al., Biochem. Biophys. Res. 243, 503 (1998), Rosen et al., J. Biol. Chem., 261, 13754 (1986), Bolen et al., Proc. Nati Acad. Sci. USA, 84, 2251 (1987), asaki et al., Hepatology, 27, 1257 (1998), Biscardi et al., Adv. Cancer Res., 76, 61 (1999), Lynch et al., Leukemia, 7, 1416 (1993). In addition, the antisense Src expressed in the colon and ovarian tumor sites has been shown to inhibit tumor growth. Wiener et al 1., Clin. Cancer Res., 5, 2164 (1999), Staley et al., Cell Growth Diff., 8, 269 (1997). Other kinases of the Src family are also potential therapeutic targets. Lck plays an important role in the signaling of the T cell. Mice lacking the Lck gene have a poor ability to develop thymocytes. The role of Lck as a positive activator of T cell signaling suggests that Lck inhibitors may be useful for treating an autoimmune disease such as rheumatoid arthritis. Molina et al., Nature, 357, 161 (1992). Hck, Fgr and Lyn have P03 / 125-VPI identified as important mediators of integrin signaling in leukocytes of the spine. Lowell et al., J. Leukoc. Biol. , 65, 313 (1999). The inhibition of these kinase mediators may therefore be useful in treating inflammation. Boschelli et al., Drugs of the Future 2000, 25 (7), 717, (2000). Glycogen synthase kinase-3 (GSK-3) is a serine / threonine protein kinase that is constituted by isoforms a and ß that each is encoded by different genes [Coghlan et al., Chemistry & Biology, 7, 793-803 (2000), Kim and Kimmel, Curr. Opinion Genetics Dev., 10, 508-514 (2000)]. GSK3 has been implicated with several diseases including diabetes, Alzheimer's disease, CNS sel disorders, such as manic-depressive disorder and neurodegenerative diseases and cardiomyocete hypertrophy [WO 99/65897, WO 00/38675 and Haq et al., J. Cell Biol. (2000) 151, 117]. These diseases can be caused or resulting from the abnormal operation of certain signaling pathways of the cell in which the GSK-3 acts. It has been found that GSK-3 undergoes phosphorylation and modulates the activity of several regulatory proteins. These include glycogen synthase which is the index that limits the enzyme necessary for the synthesis of glycogen, the Tau protein associated with the microtubule, the ß-catenin factor of transcription to the gene, the factor elF2B PC3 / 125-VPI of initiation of the translation, as well as the ATP citrate lilase, axin, factor-1 of heat shock, c-Jun, c-Myc, c-Myb, CREB and CEPBa. These various objectives involve GSK-3 in many aspects of metabolism, proliferation, differentiation and cell development. In a trajectory mediated by GSK-3 that is relevant for the treatment of type II diabetes, insulin-induced signaling leads to the assimilation of cellular glucose and glycogen synthesis. Normally, the presence of insulin causes the inhibition of phosphorylation mediated by GSK-3 and the deactivation of glycogen synthase. The inhibition of GSK-3 leads to the increased synthesis of glycogen and the assimilation of glucose [Klein et al., PNAS, 93, 8455-9 (1996), Cross et al., Bioche. J., 303, 21-26 (1994), Cohen, Biochem. Soc. Trans., 21, 555-567 (1993), Masillon et al., Biochem J. 299, 123-128 (1994)]. However, in a diabetic patient where the response to insulin is impaired, glycogen synthesis and glucose uptake does not increase despite the presence of high levels of insulin in the blood. This leads to abnormally high blood levels of glucose with acute and long-term effects that can ultimately result in cardiovascular disease, kidney failure or blindness. In these patients, the normal inhibition induced P03 / 125-VPI by the insulin of GSK-3 does not occur. It has also been reported that in patients with type II diabetes, GSK-3 is overestimated [WO 00/38675]. The therapeutic inhibitors of GSK-3 are therefore potentially useful for treating diabetic patients suffering from impaired insulin response. The activity of GSK-3 has also been associated with Alzheimer's disease. This disease is characterized by the well-known β-amyloid peptide and the formation of intracellular neurofibrillary tangles. The neurofibrillary tangles contain the hyperphosphorylated Tau protein where Tau undergoes phosphorylation at abnormal sites. GSK-3 has been shown to be able to phosphorylate these abnormal sites in cells and in animal models. In addition, inhibition of GSK-3 has been shown to prevent hyperphosphorylation of Tau in cells [Lovestone et al., Current Biology 4, 1077-86 (1994), Brownlees et al., Neuroreport 8, 3251-55 (1997)] . Therefore, it is believed that the activity of GSK-3 can promote the generation of neurofibrillary tangles and the progression of Alzheimer's disease. Another substrate of GSK-3 is β-catenin which degrades after phosphorylation by GSK-3. Reduced levels of β-catenin have been reported in schizophrenic patients and have also been associated with P03 / 125-VPI other diseases that are related to the increase in neurocellular death [Zhong et al., Nature, 395, 698-702 (1998), Takashima et al., PNAS, 90, 7789-93 (1993), Pei et al., J. Neuropathol. Exp, 56, 70-78 (1997)]. The cyclin-dependent kinases (CDKs) are serine / threonine protein kinases consisting of a terminal amino lobe rich in β-sheet and a greater carboxy-terminal lobe that is largely helical. The CDKs show 11 subdomains shared by all protein kinases and vary in molecular mass from 33 to 44 kD. This family of kinases, which includes CDK1, CDK2, CDK4, and CDK6, requires phosphorylation at the residue corresponding to CDK2 Thrl60 to be fully activated [Meijer, L., Drug Resistan.ee Updates, 3, 83-88 (2000) ] Each CDK complex is formed of a regulatory cyclin subunit (eg, cyclin A, Bl, B2, DI, D2, D3, and E) and a catalytic kinase subunit (eg, CDK1, CDK2, CDK, CDK5, and CDK6). ). Each different kinase / cyclin pair functions to regulate the different and specific phases of the cell cycle known as Gl, S, G2 and M phases [Nigg, E., Nature Revlews, 2, 21-32 (2001), Flatt, P. , Pietenpol, J., Drug Metabolism Reviews, 32, 283-305 (2000)]. CDKs have been implicated with cell proliferation disorders, in particular with cancer. The P03 / 125-VPI cell proliferation is a result of direct or indirect deregulation of the cell division cycle and CDKs play a crucial role in the regulation of different phases of this cycle. For example, overexpression of cyclin DI is commonly associated with several human cancers including breast cancer, colon cancer, carcinomas and hepatocellular gliomas [Flatt, P., Pietenpol, J., Drug Metabolis Reviews, 32, 283- 305 (2000)]. The CDK2 / cyclin E complex plays a key role in the progression of early Gx in the S phases of the cell cycle and overexpression of cyclin E has been associated with different solid tumors. Therefore, inhibitors of cyclins DI, E or their associated CDKs are useful targets for cancer therapy [Kaubisch, A., Schwartz, G., The Cancer Journal, 6, 192-212 (2000)]. CDKs, especially CDK2, also play a role in apoptosis and T cell development. CDK2 has been identified as a key regulator of thymocyte apoptosis [Williams, O., et al., European Journal of Immunology, 709-713 (2000)]. The stimulation of CDK2 kinase activity is associated with the progression of apoptosis in thymocytes, in response to the specific stimulus. The inhibition of CDK2 kinase activity blocks this apoptosis which results in the protection of thymocytes.
P03 / 125-VPI In addition to cell cycle regulation and apoptosis, CDs are directly involved in the transcription process. Numerous viruses require CDKs for their replication process. Examples where CDK inhibitors restrict viral replication include human cytomegacovirus, herpes virus and varicella-herpes aberrant virus [Meijer, L. , Drug Resístanse Updates, 3, 83-88 (2000)]. The inhibition of CDK is also useful for the treatment of neurodegenerative disorders such as Alzheimer's disease. The appearance of Paired Helical Filaments (PHF), associated with Alzheimer's disease, is caused by the hyperphosphorylation of the Tau protein by CDK5 / p25 [Meijer, L., Drug Resístanse Updates, 3, 83-88 (2000)]. As a result of the biological importance of protein kinases, there is an interest today in therapeutically effective protein kinase inhibitors. As inhibitors of the protein kinase, certain aryl-substituted 2-aminopyrimidines are known. See [U.S. Patents 5,958,935, 5,863,924, 5,612,340 and PCT publication WO 01/29009]. As a consequence, there is still a great need to develop potent inhibitors of the kinases of the iUSTKs and Src families, including inhibitors P03 / 125-VPI of J K3, Src and Lck and of GSK3 and inhibitors of CDK2 that are useful to treat different diseases or conditions associated with the activation of JNK3, Src, Lck, GS 3 and CD 2.
SUMMARY OF THE INVENTION It has now been found that the compounds of this invention and pharmaceutical compositions thereof are effective as inhibitors of the N-terminal c-Jun kinases (JNK), Src, Lck, GSK3 and CDK2. These compounds have the general formulas I and II: or pharmaceutically acceptable derivatives thereof, wherein W is nitrogen or CH and R1, R2, R3 and R4 are as described below. These compounds and pharmaceutical compositions thereof are useful for treating or preventing a variety of disorders, such as heart disease, diabetes, Alzheimer's disease, immunodeficiency disorders, inflammatory diseases, allergic diseases, P03 / 125-VPI autoimmune diseases, destructive bone disorders such as osteoporosis, proliferative disorders, infectious diseases and viral diseases. The compositions are also useful in methods to prevent cell death and hyperplasia and can therefore be used to treat or prevent reperfusion / ischemia is stroke, heart attack and organ hypoxia. The compositions are also useful in methods for preventing platelet aggregation induced by thrombin. The compositions in particular are useful for disorders such as chronic myelogenous leukemia (CML), rheumatoid arthritis, asthma, osteoarthritis, ischemia, cancer and liver diseases including hepatic ischemia, heart disease such as myocardial infarction and congestive heart failure, pathological immune conditions that involve T cell activation and neurodegenerative disorders.
DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a compound of formula I or II: P03 / 125-VPI or a pharmaceutically acceptable derivative thereof, wherein: each W is independently selected from nitrogen or CH; each R1, R2 and R3 is independently selected from halogen, QR, Q (n) CN, Q (n) N02 or Q (n> Ar2; wherein: R1 and R2 or R2 and R3 are taken together optionally to forming a 4-8 membered ring saturated, partially unsaturated, or completely unsaturated, having 0-3 heteroatoms independently selected from nitrogen, oxygen or sulfur: n is zero or one Q is an alkylidene chain of Ci_4, wherein the methylene unit of Q is optionally substituted by O, S, NR, NRCO, NRCONR, NRC02, CO, C02, CONR, OC (0) NR, S02, S02 R, NRS02, NRS02NR, C (O) C ( 0) or C (0) CH2C (O); each R is independently selected from P03 / 125-VPI hydrogen or an optionally substituted C1-C4 aliphatic group, wherein: two Rs attached to the same nitrogen atom are optionally taken together with the nitrogen atom to form a saturated 3-7 membered ring, partially not saturated, or completely unsaturated, having 1-2 additional heteroatoms independently selected from nitrogen, oxygen or sulfur; R4 is Ar1, T-Ar2 or T (n) -Ar3; T is an alkylidene chain of Ca_2, wherein a methylene unit of T is optionally replaced by O, NR, NRCO, NRCONR, NRC02, CO, C02, CONR, OC (0) NR, S02, S02NR, NRS02, NRS02NR, C (0) C (0) or C (0) CH2C (0); Ar1 is a 5-6 member monocyclic or bicyclic ring system of 8-10 members, saturated, partially unsaturated, or completely unsaturated; wherein: Ar1 is optionally substituted with up to five substituents, wherein the first substituent is selected from Rx or R5, and wherein the additional substituents are independently selected from R5; each R is independently selected from a 5-6 membered aryl ring, having 0-3 heteroatoms selected from nitrogen, oxygen or sulfur, wherein: P03 / 12S-VPI Rx is optionally substituted with 1-3 R5; each R5 is independently selected from R, halogen, N02 / CN, OR, SR, N (R) 2, NRC (0) R, RC (0) N (R) 2 / NRC02R, C (0) R, C02R, C (0) N (R) 2, OC (0) N (R) 2 SOR, S02R, S02N (R) 2, NRS02R, NRS02N (R) 2, C (0) C (0) R or C (O) C¾C (O) R; Ar2 is a 5-6 membered monocyclic ring, saturated, partially unsaturated, or completely unsaturated, having 0-3 heteroatoms independently selected from nitrogen, oxygen or sulfur, or an 8-10 membered bicyclic ring system, saturated, partially unsaturated, or completely unsaturated, having 0-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur; wherein: Ar2 is optionally substituted with up to five substituents, wherein the first substituent is selected from R or R5, and wherein any additional substituents are independently selected from Rs; Ar3 is a 6-membered aryl ring, having 0-2 nitrogens, wherein: Ar3 is substituted with a group Z-R6 and is optionally substituted with 1-3 R5; Z is an alkylidene chain of Ca-C6, where up to two non-adjacent methylene units of Z are optionally replaced by CO, C02, COCO, CONR, OCO R, NRNR, NRNRCO, NRCO, NRC02, NRCONR, SO, S02, NRS02, S02NR, P03 / 125-VPI NRS02NR, O, S or NR; and R6 is selected from Ar2, R, halogen, N02, CN, OR, SR, N (R) 2 / NRG (0) R, NRC (0) N (R) 2, NRC02R, C (0) R, C02R , 0C (0) R, C (0) N (R) 2, 0C (0) N (R) 2, SOR, S02R, S02N (R) 2, NRS02R, NRS02N (R) 2, C (O) C (0) R or C (0) C¾C (O) R; with the proviso that: (i) when R 4 is phenyl substituted with two ORs, where R is not hydrogen, the two ORs occupy different positions on the phenyl ring of simultaneously meta and para; and (ii) the compound is different from a compound of formula III wherein: A is a phenyl ring substituted with one or more groups selected from halogen, CN, 0C (0) N¾, C02R10, COR10, SO2N (R10) 2, N (R10) 2, OR10, or fluoroalkyl, wherein each R10 is independently selected from hydrogen or an alkyl group of Ca-C7, substituted P03 / 125-VPI optionally with NH 2 / NH (C 1 -C 7 alkyl) or (C 1 -C 7 alkyl) 2; and B is selected from halogen, CN, OC (0) H2, C02R10, COR10, SO2N (R10) 2, N (R10) 2, OR10 or fluoro- (C1-C7 alkyl). As used herein, the following definitions should apply, unless otherwise indicated. The phrase "optionally substituted" is used interchangeably with the phrase "substituted or unsubstituted". Unless otherwise indicated, an optionally substituted group may have a substituent at each substitutable position in the group, and each substitution is independent of the other. The term "aliphatic" or "aliphatic group" as used herein, means a straight or branched chain hydrocarbon chain of C1-C12, which is completely saturated or which contains one or more units of unsaturation, or a C3 monocyclic hydrocarbon -Ca or a C8-C12 bicyclic hydrocarbon, which is completely saturated, or which contains one or more units of unsaturation, but which is not aromatic (also referred to herein as "carbocycle" or "cycloalkyl"), which has only one point of binding to the rest of the molecule, wherein any single ring in the bicyclic ring system has 3-7 members. For example, suitable aliphatic groups include, so P03 / 125-exclusive VPI, linear or branched groups of alkyl, alkenyl, alkyl and hybrids thereof, such as (cycloalkyl) alkyl, (cycloalkenyl) alkyl or (cycloalkyl) alkenyl. The terms "alkyl", "alkoxy", "hydroxyalkyl", "alkoxyalkyl" and "alkoxycarbonyl", used alone or as part of a larger portion, include linear and branched chains containing from one to twelve carbon atoms. The terms "alkenyl" and "alkynyl" used alone or as part of a larger portion should include linear and branched chains containing from two to twelve carbon atoms. The terms "haloalkyl", "haloalkenyl" and "haloalkoxy" mean alkyl, alkenyl or alkoxy, whichever is the case, substituted with one or more halogen atoms. The term "halogen" means F, Cl, Br or I. The term "heteroatom" means nitrogen, oxygen or sulfur and includes any oxidized form of nitrogen and sulfur, and the quaternized form of any basic nitrogen. Also, the term "nitrogen" includes a substitutable nitrogen of a heterocyclic ring. As an example, in a saturated or partially unsaturated ring having 0-3 heteroatoms selected from oxygen, sulfur or nitrogen, the nitrogen may be N (as P03 / 125-VPI in 3, 4-dihydro-2H-pyrrolyl), NH (as in pyrrolidinyl) or NR + (as in the substituted N-pyrrolidinyl). The term "aryl" used alone or as part of a larger portion, as in "aralkyl", "aralkoxy", or "aryloxyalkyl", refers to monocyclic, bicyclic and tricyclic ring systems, having a total of five to fourteen members in the ring, wherein at least one ring in the system is aromatic, and wherein each ring in the system contains from 3 to 7 ring members. The term "aryl" can be used interchangeably with the term "aryl ring". The term "aryl" also refers to heteroaryl ring systems, as defined herein below. The term "ethercycle", "heterocyclyl", or "heterocyclic", as used herein, means non-aromatic, monocyclic, bicyclic or tricyclic ring systems, having from five to fourteen members in the ring, in which one or more ring members is a heteroatom, wherein each ring in The system contains 3 to 7 ring members. The term "heteroaryl", used alone or as part of a larger portion, as in "heteroaralkyl" or "heteroarylalkoxy", refers to monocyclic, bicyclic and tricyclic ring systems, which have a total P03 / 125-VPI from five to fourteen members in the ring, where at least one ring in the system is aromatic, at least one ring in the system contains one or more heteroatoms, and wherein each ring in the system contains from 3 to 7 ring members. The term "heteroaryl" can be used interchangeably with the term "heteroaryl ring" or the term "heteroaromatic". An aliphatic group or a non-aromatic heterocyclic ring may contain one or more substituents. Suitable substituents on the saturated carbon of an aliphatic group or a non-aromatic heterocyclic ring are selected from halogen, oxo, -R °, -0R °, -SR °, 1,2-methylene-dioxy, 1,2-ethylenedioxy , phenyl (Ph) optionally substituted with R °, -O (Ph) optionally substituted with R °, -CH2 (Ph) optionally substituted with R °, -CH2CH2 (Ph), optionally substituted with R °, -N02, -CN , -N (R °) 2, -NR ° C (0) R °, ~ JSrR ° C (0) N (R °) 2, -NR ° C02R °, -NR ° NR ° C (0) R ° , -NR ° R ° C (0) N (Ro) 2, -NR ° NR ° C02R0, ~ C (0) C (0) R °, -C (0) CH2C (0) R °, -C02R °, -C (0) R °, -C (0) N (R °) 2, -0C (0) N (R °) 2, -S (0) 2R °, -S02N (R °) 2, -S (0) R °, -NR ° S02N (R °) 2, -NR ° S02R °, -C (= S) N (R °) 2 , -C (= NH) -N (R °) 2, = S, = MHR °, = NN (R °) 2, = MNHC (0) R °, = KNHC02 (alkyl), = KNHS02 (alkyl), = NR ° or - (CH2) and MHC (0) R °, wherein each R ° is independently selected from hydrogen, an aliphatic group of Ci_6 optionally substituted, a heteroaryl ring of 5-6 P03 / 125-VPI unsubstituted or heterocyclic members, phenyl, -O (Ph) or -C¾ (Ph). The optional substituents in the aliphatic group of R ° are selected from NH2, HH (aliphatic group of Ci_4), N (aliphatic group of 02-4) 2, halogen, aliphatic group of C2-4, OH, O (aliphatic group of Ci_4), N02, CN, C02H, C02 (aliphatic group of 02-4), O (haloalicytic group of C -4) or a haloaliphatic group of C2-4. The term "alkylidene chain" refers to a linear or branched carbon chain, which may be completely saturated or may have one or more units of unsaturation. A combination of substituents or variables is permissible only if such combination results in a stable or chemically feasible compound. A stable compound or a chemically feasible compound is one that is not substantially altered when a temperature of 40 ° C or less is maintained, in the absence of moisture or other chemically reactive conditions, for at least a week. It will be apparent to one of ordinary skill in the art that certain compounds of this invention can exist in tautomeric forms, all those tautomeric forms of the compounds are within the scope of the invention. Unless otherwise indicated, the structures described here are also intended to include all P03 / 125-VPI the stereochemical forms of the structure; that is, the R and S configurations for each asymmetric center. Therefore, the unique stereochemical isomers, as well as the enantiomeric and diastereomeric mixtures of the present compounds, are within the scope of the invention. Unless otherwise indicated, the structures described herein are also intended to include compounds that differ only by the presence of one or more isotopically enriched atoms. For example, compounds having the present structures, except for the replacement of a hydrogen by a deuterium or a tritium, or the replacement of a carbon by a carbon enriched with 3C or 14C, are within the scope of this invention. Preferred groups R1, R2 and R3 of formula I and II, are selected from halogen, QR or QAr2, wherein Q is an alkylidene chain of < ¾_3 wherein a methylene unit of Q is optionally replaced by -O-, -S-, -NHCO- or -NR- and Ar2 is an optionally substituted 5-6 membered ring, saturated, partially unsaturated, or completely unsaturated , which has 0-2 heteroatoms, independently selected from nitrogen, oxygen or sulfur. The most preferred R1, R2 and R3 groups are selected from OH, OCH3, 0CH2CH3, HCOMe, N¾, NH (aliphatic group of ¾_4), N (aliphatic group of ¾_4) 2, P03 / 125-VPI 0 (CH2) 2morpholin-4-yl, 0 (CH2) 2NH2, O (CH2) 2NH (aliphatic group of Ca_), 0 (CH2) 2N (aliphatic group of Ci-4) 2, bromine, chlorine or fluoro. Other preferred compounds of formulas I and II are those wherein R1 and R2 or R2 and R3 are taken together to form The most preferred Ar2 groups are morpholin-4-yl, pyrrolidin-1-yl, piperidin-1-yl, thiomorpholin-4-yl, pyrazol-1-yl or imidazol-1-yl. Preferred R4 groups of formulas I and II are selected from a 6-membered, saturated, partially unsaturated ring, or an aryl having 0-3 nitrogens, a 9-10 membered bicyclic aryl ring having 0-2 nitrogens , or a 5-membered heteroaryl ring having 2-3 heteroatoms independently selected from nitrogen, oxygen or sulfur, wherein each ring is optionally substituted. The most preferred R4 groups of formulas I and II are substituted rings selected from phenyl, cyclohexyl, naphthyl, pyridyl, P03 / 125-VPI pyrimidinyl, triazinyl, thiazolyl, thiadiazolyl, pyrazolyl, isoxazolyl, indazolyl or benzimidazolyl. Preferred substituents on R4 are independently selected from R, halogen, N02, OR, N (R) 2, x or Z-Rs, wherein R is hydrogen or an aliphatic group of Ci_4 optionally substituted. The preferred Z groups of formulas I and II, are selected from an alkylidene chain of (¼_4, wherein a methylene unit of Z is optionally replaced by -0-, -S-, -S02- or -NH-. Preferred R6 are selected from phenyl, pyridyl, and optionally substituted pyrimidinyl Rx substituents preferred in R4 are selected from phenyl, pyridyl, and pyrimidinyl, wherein Rx is optionally substituted with 1-2 R5. Most preferred substituents in R4 are selected of chlorine, fluoro, bromo, methyl, ethyl, t-butyl, isopropyl, cyclopropyl, nitro, OMe, OEt, CF3, NH2, benzyl, benzyloxy, OH, methylenedioxy, S02NH2, phenoxy, O-pyridinyl, S02phenyl, nitrophenoxy, aminophenoxy , S-dimethylpyrimidine, NH-phenyl, NH-methoxyphenyl, pyridinyl, aminophenyl, phenol, chloro-fluoro-phenyl, dimethylaminophenyl, CF3-phenyl, dimethylphenyl, chlorophenyl, fluorophenyl, methoxyphenoxy, chlorophenoxy, ethoxyphenoxy and fluorophenoxy. I and II are here described in Tables 1, 2 and 3.
P03 / 125-VPI A preferred embodiment relates to a compound of formula I-a or II-a: Or a pharmaceutically acceptable derivative thereof, wherein R1, R3, R4, Q? Ar2 are as defined above. Preferred R1, R3, R4, Ar2 and Q are as described above for the compounds of formulas 1 and II. The most preferred compounds of formula I-a and II-a are those of formula I-a 'and II-a': or a pharmaceutically acceptable derivative thereof, in P03 / 125-VPI where R1, R3 and R4 are as defined above. Preferred groups R1, R3 and R4 of the formulas I-a 'and II-a' are those described above for the compounds of formula I and II. Another preferred embodiment relates to a compound of formula I-b or Il-b: or a pharmaceutically acceptable derivative thereof, wherein R1, R2, R3, Z and R6 are as defined above. Preferred R1, R2, R3, Z and R6 are as described above for the compounds of formulas I and II. The exemplary structures of formula I, wherein W is nitrogen, are set forth in Table 1 below.
P03 / 125-VPI Table 1. Compounds of Formula I P03 / 125-VPI P03 / 125-VPI P03 / 125-VPI P03 / 125-VPI P03 / 125-VPI P03 / 125-VPI P03 / 125-VPI P03 / 125-VPI P03 / 125-VPI P03 / 125-VPI P03 / 125-VPI P03 / 12S-VPI P03 / 125-VPI P03 / 125-VPI P03 / 125-VPI P03 / 125-VPI P03 / 125-VPI Exemplary structures of formula I, wherein W is CH, are set forth in Table 2 below. P03 / 12S-VPI P03 / 12S-VPI P03 / 125-VPI P03 / 125-VPI P03 / 125-VPI P03 / 125-VPI P03 / 125-VPI P03 / 25-VPI P03 / 12S-VPI P03 / 125-VPI No. R4 1-145 OMe 1-146 OMe 1-147 OMe 1-148 OMe 1-149 OMe P03 / 125-VPI P03 / 125-VPI P03 / 125-VPI The exemplary structures of formula II, wherein W is nitrogen, are set forth in Table 3 below.
Table 3. Compounds of Formula II P03 / 125-VPI P03 / 125-VPI P03 / 125-VPI P03 / 125-VPI P03 / 125-VPI P03 / 125-VPI P03 / 125-VPI PC3 / 125-VPI P03 / 125-VPI P03 / 125-VPI P03 / 125-VPI P03 / 12S-VPI P03 / 125-VPI P03 / 125-VPI E03 / 125-VPI P03 / 125-VPI P03 / 125-VPI P03 / 125-VPI The present compounds can be prepared in general, by methods known to those skilled in the art for analogous compounds, as illustrated by general Reaction Schemes I to IV, and the synthetic examples shown below.
P03 / .. 25-VPI Reagents and conditions: (a) MeMgCl, THF, -78 ° C; (b) Mn02, CH2C12, reflux; Reaction Scheme I above shows a general synthetic route used to prepare intermediate compound 2_. To a solution of aldehyde (i) in THF, at -78 ° C, a solution of methyl magnesium chloride in THF is added. The reaction is quenched with cold HCl (1N), then the aqueous workup, followed by chromatography, provides the alcohol (ii). Manganese dioxide is added to a solution of ii in C¾C12, and the resulting mixture is heated to reflux. After 3 hours, the suspension is filtered through Celite® and the filtrate is concentrated in vacuo to provide the ketone (3_).
Reaction Scheme II P03 / 125-VPI Reagents and conditions: (a) NH2NCN, HCl, 1,4-dioxane; (b) DMF-DMA, 80 ° C, 12-18 hours; (c) acetonitrile, reflux. The reaction scheme II above shows a general synthetic route used to prepare compounds of formula I. The aniline 1 is combined with cyanamide, HCl (4N in 1,4-dioxane), and 1,4-dioxane in a sealed tube, and the resulting mixture is heated to 60 ° C. After 12-18 hours, the aqueous treatment provides the desired guanidine derivative (2). Intermediate 4 is prepared by dissolving 3_ in?,? - dimethylformamide dimethylacetal (DMF-DMA), and heating the resulting solution to 80 ° C. The reaction was concentrated in vacuo, and the crude product recrystallized to P03 / 125-VEI provide enaminone 4_. Enaminone 4 was combined with guanidine 2_ and acetonitrile and the resulting mixture was heated to 80 ° C. After the accusative treatment, the crude product is purified by chromatography to provide I in a yield of 50-95%, depending on the guanidine derivative used. A variety of 1, R2, R3 and R4, are suitable for the reaction conditions described above for Reaction Scheme II, including those listed above in Table 1.
Reaction Scheme III Reagents and conditions: (a) Mg, I2, THF, trimethyl borate; P03 / 125-VPI room temperature, 12-18 hours; (b) Na2CO3, Pd (PPh3) 4, toluene: methane1 (4: 1), reflux, 24 hours; (c) NaH (60% dispersion in mineral oil), Pd (PPh3) 4, THF, reflux, 3 hours. Reaction Scheme III above shows an alternative method for preparing the compounds of formula I. The aryl boronic acid (6) is prepared from the treatment of bromide iii with magnesium chips, and a catalytic amount of iodine in THF at reflux for 12- 18 hours. The reaction is cooled to 0 ° C, then trimethyl borate is added and the resulting mixture is stirred at room temperature for 12-18 hours. The reaction is hydrolyzed with HC1 (6N, aqueous) at 60 ° C, then the aqueous workup provides the desired boronic acid 6. Boronic acid 6_ is combined with dichloropyrimidine (5), Na 2 CO 3, and Pd (PPh 3) 4 in a solution of toluene: methano1 (4: 1). The resulting mixture is refluxed for 24 hours, then filtered through silica gel. The crude product is purified by flash chromatography to provide chloropyrimidine 1_. Chloropyrimidine 1_ is combined with aniline 1, NaH (60% dispersion in mineral oil), and Pd (PPh3) 4 in THF, and the resulting mixture is refluxed for 3 hours. The reaction is cooled, then poured into P03 / 125-VPI water. Aqueous work, followed by flash chromatography, provides I. A variety of R1, R2, R3, and R4, lends itself to the reaction conditions described above for Reaction Scheme III, including those listed above in Table 1. The compounds of formula I, wherein W is CH, can also be synthesized by methods essentially similar to those described above in Reaction Scheme III, by methods shown in Reaction Scheme IV below, and by methods known to one of skill in the art. The technique.
Reaction Scheme IV Lithium hexamethyldisilacide, THF, then chloride P03 / 125-VPI trimethylsilyl; (c) dimethylformamide dimethylacetal; (d) gaseous HBr, CHC13; e) RNH2, NaH, dimethylformamide, 80 ° C. The details of the conditions used to produce these compounds are set forth in the Examples. Persons with ordinary experience in this technical field will be able to synthesize other compounds of the invention by following the teachings of this description and using reagents that are already synthesized or that can be obtained commercially. The activity of a compound used in this invention as an inhibitor of J K3, GSK-3, CD2, Lck or Src, of this invention can be analyzed in vi tro, in vivo or in a cell line. In vitro analyzes include analyzes that determine the inhibition of either the phosphorylation activity or the ATPase activity of activated JNK3, GSK-3, CDK2, Lck or Src. Alternate in vitro assays quantify the ability of the inhibitor to bind to JTSTK3, GSK-3, CDK2, Lck or Src. The linker of the inhibitor can be measured either by radiolabelling the inhibitor before binding, by isolating the inhibitor complex / J K3, inhibitor / GSK-3, inhibitor / CDK2, inhibitor / Lck or inhibitor / Src and determining the amount of the linked radiolabel. Alternatively, the inhibitor link can be determined by conducting a competition experiment where new inhibitors are incubated with J K3, P03 / 125-VPI GSK-3, CDK2, Lck or Src linked to known radioligands. According to another embodiment, the invention provides a composition comprising a compound of this invention or a pharmaceutically acceptable salt of the invention and a pharmaceutically acceptable carrier, adjuvant or vehicle. The amount of the compound in these compositions of this invention is effective to perceptibly inhibit a protein kinase, particularly JK3, GSK-3, CDK2, Lck or Src in a biological sample or in a patient. Preferably, the composition of this invention is formulated by administration to a patient in need of said composition. More preferably, the composition of this invention is formulated for oral administration to a patient. The term "patient" used herein, refers to an animal, preferably a mammal and more preferably a human. The term "pharmaceutically acceptable carrier, adjuvant or vehicle" refers to a non-toxic carrier, adjuvant or vehicle that does not destroy the pharmacological activity of the compound with which it is formulated. The pharmaceutically acceptable carrier, adjuvant or vehicle that can be used in the compositions of this invention include P03 / 125-VPI unrestricted to ion exchangers, alumina, aluminum stearate, lecithin, whey proteins, such as human serum albumin, buffer substances such as phosphates, glycine, sorbic acid, potassium sorbate, partial mixtures of glyceride of fatty acids saturated vegetables, water, salts or electrolytes, such as protamine sulphate, sodium dibasic phosphate, potassium monobasic phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinylpyrrolidone, cellulose-based substances, polyethylene glycol, carboxymethylcellulose of sodium, polyacrylates, waxes, polymers of polyethylene-polyoxypropylene block, polyethylene glycol and wool grease. The term "perceptibly inhibited", as used in the present invention means a change in the activity of JNK3, GSK-3, CDK2, Lck or Src between a sample comprising said composition and a JTSTK3, GSK-3 kinase. , CDK2, Lck or Src and an equivalent sample comprising the kinase of JNK3, GSK-3, CDK2, Lck or Src in the absence of said composition. A "pharmaceutically acceptable salt" means, salt, ester, salt of an ester or other pharmaceutically acceptable derivative of a compound of this invention which, after administration to a recipient, is capable of providing, either directly or indirectly, a P03 / 125-VPI compound of this invention or an active metabolite as an inhibitory agent or a residue thereof. Pharmaceutically acceptable salts of the compounds of this invention include those derived from pharmaceutically acceptable organic and inorganic acids and bases. Examples of suitable acid salts include acetate, adipate, alginate, aspartate, benzoate, benzene sulfonate, bisulfate, butyrate, citrate, camforate, camphorsulfonate, cyclopentanpropionate, digluconate, dodecyl sulfate, ethanesulfonate, formate, fumarate, glucoheptanoate, glycerol phosphate, glycolate, hemisulfate, heptanoate, hexanoate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethane sulfonate, lactate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oxalate, palmoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, salicylate, succinate, sulfate, tartrate, thiocyanate, tosylate and undecanoate. Other acids, such as oxalic, while not in themselves pharmaceutically acceptable, can be employed in the preparation of salts useful as intermediates in obtaining the compounds of the invention from their pharmaceutically acceptable addition salts. Salts derived from appropriate bases include alkali metal salts (eg, sodium and potassium), P03 / 12S-VPI alkaline earth metal salts (for example, magnesium), ammonium salts and N + salts (0 to 4 alkyl) 4. This invention also visualizes the quaternization of any of the basic nitrogen containing groups of the compounds described herein. Dispersible or oil-soluble or water-soluble products can be obtained by such quaternization. The compositions of the present invention can be administered orally, parenterally, by inhalation, roosting, topically, rectally, nasally, buccally, vaginally or via an implanted reservoir. The term "parenteral" as used herein includes subcutaneous, intravenous, intramuscular, intra-articular, intrasynovial, intra-sternal, intrathecal, intrahepatic, intralesional and intracarnial injection or infusion techniques. Preferably, the compositions are administered orally, intraperitoneally or intravenously. The sterile injectable forms of the compositions of this invention can be aqueous or oleaginous suspensions. These suspensions may be formulated according to techniques known in the art using suitable dispersing agents and wetting agents and suspending agents. The sterile injectable preparation can also be a solution or a sterile injectable suspension in a parenterally acceptable diluent or solvent P03 / 125-VPI non-toxic, for example as a solution in 1,3-butanediol. Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution, and isotonic sodium chloride solution. In addition, fixed oils, conventionally sterile, are used as a solvent or suspension medium. For this purpose, any soft fixed oil including synthetic mono- or di-glycerides can be employed. Fatty acids, such as oleic acid and its glyceride derivatives are useful in the preparation of injectables, as are natural pharmaceutically acceptable oils, such as olive oil or castor oil, especially in their polyoxyethylated versions. These oil solutions or suspensions may also contain a long chain alcohol diluent or dispersant, such as carboxymethyl cellulose or similar dispersing agents that are commonly used in the formulation of pharmaceutically acceptable dosage forms including emulsions or suspensions. Other commonly used surfactants (surfactants), such as Tweens, Spans and other emulsifying agents or bioavailability enhancers commonly used in the manufacture of solid, liquid and other pharmaceutically acceptable dosage forms can also be used for formulation purposes.
P03 / 125-VPI The pharmaceutically acceptable compositions of this invention can be administered orally in any orally acceptable dosage form including, but limited to, capsules, tablets, suspensions or aqueous solutions. In the case of tablets for oral use, commonly used carriers include lactose and corn starch. Lubricating agents, such as magnesium stearate, are also typically added. For oral administration in a capsule form, useful diluents include lactose and dried corn starch. When aqueous suspensions are required for oral use, the active ingredient is combined with emulsifying agents and suspending agents. If desired, certain sweetening agents, flavoring agents or coloring agents can also be used. Alternatively, the pharmaceutically acceptable compositions of this invention can be administered in the form of suppositories for rectal administration. These can be prepared by mixing the agent with a suitable non-irritating excipient which is solid at room temperature but is liquid at the rectal temperature and will therefore melt in the rectum to release the drug. Such materials include cocoa butter, beeswax and polyethylene glycols. The pharmaceutically acceptable compositions of P03 / 125-VPI this invention can also be administered topically, especially when the purpose of the treatment includes easily accessible areas or organs for topical application, including diseases of the eye, the skin, or the lower intestinal tract. Suitable topical formulations are easily prepared for each of these areas or organs. Topical application for the lower intestinal tract can be done in a rectal suppository formulation (see above) or in a suitable enema formulation. Topically transdermal patches can also be used. For topical applications, pharmaceutically acceptable compositions can be formulated in a suitable ointment containing the active component suspended or dissolved in one or more carriers. Carriers for topical administration of the compounds of this invention include, unrestrictedly, mineral oil, liquid petrolatum, white petrolatum, propylene glycol, polyoxyethylene, polyoxypropylene compound, emulsifying wax and water. Alternatively, the pharmaceutically acceptable compositions can be formulated in a suitable lotion or cream containing the active components suspended or dissolved in one or more pharmaceutically acceptable carriers. Suitable carriers include, unrestrictedly, mineral oil, P03 / 125-VPI sorbitan monostearate, polysorbate 60, cetyl ester wax, ceteryl alcohol, 2-octyldodecanol, benzyl alcohol and water. For ophthalmic use, pharmaceutically acceptable compositions can be formulated as micronized suspensions in sterile, pH adjusted, isotonic saline or, preferably, as sterile, pH adjusted, isotonic saline solutions, either with or without a preservative such as sodium chloride. benzylalkonium Alternatively, for ophthalmic uses, pharmaceutically acceptable compositions can be formulated in an ointment such as petrolatum. The pharmaceutically acceptable compositions of this invention can also be administered by a nasal spray or inhalation. Such compositions are prepared according to techniques well known in the pharmaceutical formulation art and can be prepared as solutions in saline, using benzyl alcohol or other suitable preservatives, absorption promoters to improve bioavailability, fluorocarbons, and / or other solubilizing agents or conventional dispersing agents. Preferably, the pharmaceutically acceptable compositions of this invention are formulated for oral administration.
P03 / 125-VPI The amount of the inhibitor of the compounds of the present invention that can be combined with the carrier materials to produce a single dosage form will vary depending on the host treated, the particular mode of administration. Preferably, the compositions should be formulated so that a dosage of between 0.01-100 mg / kg body weight / day of the inhibitor can be administered to a patient receiving these compositions. It should also be understood that a specific dosage and treatment regimen for any particular patient will depend on a variety of factors, including the activity of the specific compound employed, age, body weight, general health status, sex, diet, time of administration , type of excretion, combination of the drug, and judgment of the attending physician and the severity of the particular disease to be treated. The amount of the inhibitor will also depend on the particular compound in the composition. Depending on the particular condition or disease to be treated or prevented, additional therapeutic agents, which are usually administered for the treatment or prevention of the condition are also present in the compositions of this invention.
P03 / 125-VPI For example, chemotherapeutic agents or other anti-proliferative agents can be combined with the compounds of this invention to treat proliferative diseases and cancer. Examples of chemotherapeutic agents include, unrestrictedly, Gleevec ™, adriamycin, dexamethasone, vincristine, cyclophosphamide, fluorouracil, topotecan, taxol, interferons and platinum derivatives. Other examples of the compounds of the agents of this invention that may also be combined include, among others, anti-inflammatory agents such as corticosteroids, TNF blockers, IL-1 RA, azathioprine, cyclophosphamide and sulfasalazine; immunomodulatory and immunosuppressive agents such as cyclosporine, tacrolimus, rapamycin, mycophenolate mofetil, interferons, corticosteroids, cyclophosphamide, azathioprine and sufasalazine; neurotropic factors such as acetylcholinesterase inhibitors, MAO inhibitors, interferons, anticonvulsants, ion channel blockers, riluzole and antiparkinson agents; agents for the treatment of cardiovascular diseases, such as beta blockers, ACE inhibitors, diuretics, nitrates, calcium channel blockers and statins agents for the treatment of liver diseases such as corticosteroids, cholestyramine, interferons and agents P03 / 125-VPI antivirals; agents for the treatment of blood disorders such as corticosteroids, antileukemic agents, and growth factors, agents for the treatment of diabetes such as insulin, insulin analogs, alpha glucosidase inhibitors, biguanides and insulin sensitizers; and agents for the treatment of immunodeficiency disorders such as gamma globulin. The present amount of the additional therapeutic agent in the compositions of this invention will not be greater than the amount that would normally be administered in a composition comprising the therapeutic agent only as an active agent. Preferably, the amount of the additional therapeutic agent in the compositions disclosed herein will be in a range of 50% to 100% of the amount that normally occurs in a condition comprising the agent only as a therapeutically active agent. According to another embodiment, the invention relates to a method of inhibiting the activity of kinase J K3, GSK-3, CDK2, Lck or Src in a biological sample comprising the step of contacting said biological sample with a compound of this invention, or the composition comprising said compound. The term "biological sample", as used herein, includes without limit, the cultures extracts of P03 / 125-VPI cells; biopsy material obtained or extracted from a mammal; and blood, saliva, urine, feces, semen, tears or other fluids or body extracts. The inhibition of the kinase activity JNK3, GSK-3, CDK2, Lck or Src in a biological sample is useful for a variety of purposes that are known to the person skilled in the art. Examples of such purposes include unrestricted blood transfusion, organ transplantation, storage of a biological specimen and biological analysis. According to another embodiment, the invention provides a method for treating or decreasing the severity of a disease or condition mediated by JNK3-, GSK-3-, CDK2-, Lck- or Src- in a patient comprising the step of administering to said patient a composition that is in accordance with the present invention. According to another embodiment, the present invention relates to the method of treating cancer comprising the step of blocking the transmission of cancer cells within their proliferation phase by inhibiting CDK2 with a compound that is in accordance with the present invention or a pharmaceutically acceptable composition comprising said compound. The term "JNK-mediated condition," as used herein, means any disease or other P03 / 125-VPI deterioration condition in which it is known that the NK plays a role. Such conditions include, without limitation, inflammatory diseases, autoimmune diseases, destructive bone disorders, proliferative disorders, cancer, infectious diseases, neurodegenerative diseases, allergies, reperfusion / ischemia in stroke, heart attacks, angiogenic disorders, hypoxia in organs, hyperplasia vascular, cardiac hypertrophy, platelet aggregation induced by thrombin, and conditions associated with prostaglandin endoperoxidase synthase-2. Inflammatory diseases that can be treated or prevented by the compounds of this invention include, unrestrictedly, acute pancreatitis, chronic pancreatitis, asthma, allergies, and adult respiratory distress syndrome. Autoimmune diseases that can be treated or prevented by the compounds of this invention include, unrestrictedly, glomerulonephritis, rheumatoid arthritis, systemic lupus erythematosus, scleroderma, chronic thyroiditis, Graves' disease, autoimmune gastritis, diabetes, autoimmune hemolytic anemia, autoimmune neutropenia, thrombocytopenia, atopic dermatitis, chronic active hepatitis, myasthenia gravis, multiple sclerosis, inflammatory bowel disease, P03 / 125-VPI ulcerative colitis, Crohn's disease, psoriasis, or graft-versus-host disease. Destructive bone disorders that can be treated or prevented by the compounds of this invention include, unrestrictedly, osteoporosis, osteoarthritis and bone disorders related to multiple myeloma. Proliferative diseases that can be treated or prevented by the compounds of this invention include, unrestrictedly, acute myelogenous leukemia, chronic myelogenous leukemia, metastatic melanoma, aposi sarcoma, multiple myeloma, and HTLV-1 mediated tumorigenesis. Angiogenic disorders that can be treated or prevented by the compounds of this invention include solid tumors, ocular neovasculization, infantile hemangiomas. Infectious diseases that can be treated or prevented by the compounds of this invention include, unrestrictedly, asepsis, septic trauma, and Shigellosis. Viral diseases that can be treated or prevented by the compounds of this invention include, unrestrictedly, acute hepatitis infection (including hepatitis A, hepatitis B and hepatitis C), HIV infection and CMV retinitis.
P03 / 125-VPI Neurodegenerative diseases that can be treated or prevented by the compounds of this invention include, unrestricted, Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis (ALS), epilepsy, seizures, Huntington's disease, traumatic brain injury, ischemic stroke and stroke with hemorrhages, including neurodegenerative disease driven by apoptosis, caused by traumatic injury, acute hypoxia, ischemia or glutamate neurotoxicity. "JNK-mediated conditions" also include ischemia / reperfusion in stroke, heart attacks, myocardial ischemia, hypoxia in the organ, vascular hyperplasia, cardiac hypertrophy, hepatic ischemia, liver disease, congestive heart failure, immune pathological responses such as those caused by T cell activation and platelet aggregation induced by thrombin. In addition, the compounds of the invention may be capable of inhibiting the expression of inducible pro-inflammatory proteins. Therefore, other "JNK-mediated conditions" that can be treated by the compounds of this invention include edema, analgesia, fever and pain, such as neuromuscular pain, headache, pain from cancer, dental pain and arthritis pain.
P03 / X2S-VPI The compounds of this invention are also useful as inhibitors of the Src family kinases, especially Src and Lck. For a general review of these kinases see Thomas and Brugge, ñnnu. Rev. Cell Dev. Biol. (1997) 13, 513; Lawrence and Niu, Pharmacol. Ther. (1998) 77, 81; Tatosyan and Mizenina, Biochemistry (Moscow) (2000) 65, 49. The term "disease mediated by Lck or by Src", as used herein means any disease or other deleterious condition in which Src or Lck is known to have an important function Consequently, these compounds are useful for treating diseases or conditions that are known to be affected by the activity of one or more kinases of the Src family. Such diseases or conditions include hypercalcemia, restenosis, osteoporosis, osteoarthritis, symptomatic treatment of bone metastasis, rheumatoid arthritis, inflammatory bowel disease, multiple sclerosis, psoriasis, lupus, graft-versus-host disease, T cell-mediated hypersensitivity disease. , Hashimoto's thyroiditis, Guillain-Barre syndrome, chronic obstructive pulmonary disorder, contact dermatitis, cancer, Paget's disease, asthma, ischemia or reperfusion injury, allergic disease, atopic dermatitis and allergic rhinitis. Diseases that are affected by Src's activity, in particular, include P03 / 125-VPI hypercalcemia, osteoporosis, osteoarthritis, cancer, symptomatic treatment of bone metastasis and Paget's disease. Diseases that are affected by Lck's activity, in particular, include autoimmune diseases, allergies, rheumatoid arthritis and leukemia. The term "GSK3 mediated disease", as used herein, means any disease or other deleterious condition in which GSK3 is known to perform a function. Accordingly, these compounds are useful in the treatment of diseases or conditions known to be affected by the activity of GSK3 kinase. Such diseases or conditions include diabetes, Alzheimer's, Huntington's and Parkinson's disease, dementia associated with AIDS, amyotrophic lateral sclerosis (AML), multiple sclerosis (MS). ), schizophrenia, cardiomycete hypertrophy [sic] and baldness. The term "CDK2 mediated disease," as used herein, means any disease or other deleterious condition in which CD2 is known to play a role. Accordingly, these compounds are useful in the treatment of diseases or conditions known to be affected by the activity of CDK2 kinase. Such diseases or conditions include viral infections, neurodegenerative disorders, disorders P03 / 125-IPV associated with apoptosis of thymocyte or proliferative disorders resulting from the deregulation of the cell cycle, especially the sequence of the Ga to S phase. A preferred embodiment relates to the method used to treat or prevent a disease mediated by JNK selected from inflammatory diseases, autoimmune diseases, destructive bone disorders, neurodegenerative diseases, allergies, reperfusion / ischemia in stroke, heart attacks, angiogenic disorders, hypoxia in organs, vascular hyperplasia, cardiac hypertrophy, platelet aggregation induced by the thrombin. Another preferred embodiment relates to the method used to treat and prevent a disease mediated by Lck or Src selected from hypercalcemia, osteoporosis, osteoarthritis or symptomatic treatment of bone metastasis. Another preferred embodiment relates to the method used to treat or prevent a disease mediated by GSK3 selected from diabetes, Alzheimer's disease, Huntington's disease, Parkinson's disease, multiple sclerosis (MS), or amyotrophic lateral sclerosis (AML). According to another preferred embodiment, the P03 / 125-VPI method is used to treat or prevent a disease mediated by CDK2 selected from viral infections, neurodegenerative disorders or disorders associated with thymocyte apoptosis. In addition to the compounds of this invention, the pharmaceutically acceptable derivative compounds of this invention may also be employed in compositions for treating or preventing the disorders identified above. In an alternate embodiment, the methods of this invention using the compositions that do not contain an additional therapeutic agent, comprise the additional step of separately administering to said patient an additional therapeutic agent. When these additional therapeutic agents are administered separately they must be administered to the patient prior to, sequentially with or following the administration of the compositions of this invention. The compounds of this invention or the pharmaceutical compositions herein can also be incorporated into the compositions to cover a medical device for implantation, such as prostheses, artificial valves, vascular grafts, stents and catheters. For example, vascular stents have been used to overcome restenosis (re-narrowing of the vessel wall after injury). However, patients who use stents or P03 / 125-VPI other types of implantable devices run the risk of clot formation or the activation of platelets. These undesirable effects can be prevented or mitigated by previously covering the device with a pharmaceutically acceptable composition comprising a kinase inhibitor. Appropriate coatings and the general preparation of coated implantable devices are described in U.S. Patent 6,099,562; 5,886,026 and 5,304,121. The coatings are typically made of biocompatible polymeric materials such as hydrogel polymer, polymethyldisiloxane, polycaprolactone, polyethylene glycol, polylactic acid, vinyl acetate and ethylene and mixtures thereof. Optionally, the coatings can then be covered with a suitable top layer of fluorosilicone, polysaccharides, polyethylene glycol, phospholipids or combinations thereof to share the controlled release characteristics in the composition. Implantable devices coated with a compound of this invention are another embodiment of the present invention. For the invention described herein to be fully understood, the following examples are set forth. It should be understood that these examples are for illustrative purposes only and are not in any way to be interpreted as limiting this P03 / 125-VPI invention.
EXAMPLES Example 1 1- (7-Methoxy-bezo [1,3] dioxol-5-yl) -ethanol (2): A solution of 7-methoxy-bezo [1,3] dioxol-5-carbaldehyde I) (1.8 g, 10 mmol) in THF (20 mL) was cooled to -78 ° C. A solution of raethylmagnesium chloride in THF (5.0 mL of 3M, 15 mmol) was added dropwise to the solution of i in THF. The reaction was quenched with the addition of HC1 (1N, aqueous) and extracted with ethyl acetate. The organic layer was washed with saline, dried over Na 2 SO and concentrated in vacuo. The crude product was purified by flash chromatography (silica gel: 40% -60% ethyl acetate in hexanes) to give 2 (0.89 g, 45%).
P03 / 125-VPI Example 2 1- (7-Methoxy-benzo [1,3] dioxol-5-yl) -ethanone (3): Manganese dioxide (5 g, molar excess) was added to a solution of 2 (0.89 g, 4.5 mmol) in dichloromethane (10 mL). The resulting mixture was heated to reflux for 3 hours, then filtered through Celite *. The filtrate was concentrated in vacuo to give 3_ as a dark solid.
Example 3 3-Dimethylamino-l- (7-methoxy-benzo [1,3] dioxol-5-yl) -propenone (4): It was heated at 80 ° C overnight, a solution of 3_ (0.89 g, 4.5 mmol) in?,? - dimethylformamide dimethylacetal (3.5 g, molar excess). Then the mixture of the P03 / 12S-VPI reaction to vacuum and the crude product was recrystallized from ethyl acetate / hexanes to give 4 (1.0 g, 89%).
Example 4 N-Phenyl-guanidine: A mixture of aniline (11 mmol), cyanamide (420 mg, 10 mmol) and HC1 (3 mL of 4N in dioxane, 12 mmol) was heated overnight in a sealed tube at 60 ° C. in 1,4-dioxane (10 mL). The reaction was concentrated in vacuo and the residue was partitioned between NaOH (2N) and dichloromethane. The organic layer was warmed over Na2SO4 and concentrated in vacuo to give N-phenyl-guanidine.
Example 5 1-26 P03 / 125-VPI [4- (7-Methoxy-benzo [1,3] dioxol-5-yl) -pyrimidin-2-yl] -phenyl-amine (1-26): In a sealed tube was combined, N phenyl guanidine (40 mg, excess) with 4 (50 mg, 0.2 mmol) in acetonitrile and the mixture was heated at 80 ° C overnight. After the reaction mixture was partitioned with water and ethyl acetate, the organic layer was washed with saline, dried over Na2SO4 and concentrated in vacuo. The crude product was purified by flash chromatography (silica gel, 40% ethyl acetate in hexanes) to give 1-26. "" li-NMR (CDC13, 500 MHz) d 8.40 (d, 1H), 7.69 (d, 2H), 7.43 (s, 1H), 7.35 (t, 2H), 7.21 (s, 1H), 7.05 (m , 2H), 6.07 (s, 2H), 3.99 (s, 3H).
Example 6 5 2-Chloro-4- (2, 3, 4-trimethoxyphenyl) irimidine (5): In a 250 mL round bottom flask, 1.49 grams (10 mmol) of 2,4-dichloropyrimidine was combined with acid 2.3, 4-trimethoxyphenylboronic acid (2.12 g, 10 mmol), carbonate P03 / 125-VPI sodium (2.12 g, 2 equivalents) and 1.15 g (0.1 equivalents) of tetrakis-triphenylphosphine palladium. Toluene (50 mL) and water (5 raL) were added. The reaction was allowed to reflux over nitrogen overnight. The reaction was diluted with toluene and water and the organic layer was separated, washed with saline, dried (Na2SO), filtered and concentrated to give crude pyrimidine. The compound was purified on silica gel using an eluent of 30% acetone / hexane to give 2.08 g (74%) of the product 5_ as a white solid.
Example 7 11-14 (3-Dimethylphenyl) - [4- (2, 3, 4-trimethoxyphenyl) -pyrimid-2-yl] -amine (11-14): 28 mg (100 μp) of chloropyrimidine were placed in a bottle. 5, 3,5 dimethylaniline (24 mg, 200 μp), 60% NaH (6 mg, excess), and tetrakis (triphenylphosphine) palladium (6 mg, catalytic). Tetrahydrofuran (2) was added P03 / 125-VPI mL) and the bottle was sealed and heated to reflux for two hours. The reaction was diluted with diethyl ether and washed with 1N hydrochloric acid. The organic layer was separated, washed with a solution of 1N NaOH, water and saline. The organic extract was dried (MgSO4), filtered and evaporated in vacuo to give the crude product. The compound was purified on silica gel using an eluent of 20% acetone / hexane to give the pure product 11-14 as a white solid. "" "H-NM (CDCl3, 500 MHz) d 8.41 (d, 1H), 7.78 (d, 1H), 7.35 (d, 1H), 7.31 (s, 1H), 7.08 (s, 1H), 6.82 ( d, 1H), 6.68 (s, 1?), 3.94 (s, 3H), 3.91 (s, 3H), 3.83 (s, 3H), 2.34 (s, 6H). 1- [3,4-Dimethoxy-2- (2-morpholin-4-yl-ethoxy) phenyl-ethanone (6): In a 500 mL round bottom flask, 2,3-dihydroxy-4-methoxyacetophenone (3.39 grams, 17.2 mmol) was combined with P03 / 12S-VPI 4- (2-chloroethyl) morpholine hydrochloride (3.53 grams, 19.0 mmol), 4 grams of 2C03 / and 50 mL of anhydrous DMF. The reaction was heated to 60 ° C overnight, diluted with diethyl ether and washed with 1N sodium hydroxide solution. The organic layer was washed separately, with saline, dried (Kra2SO4), filtered and concentrated in vacuo. The crude product was purified by means of flash chromatography on silica gel using an eluent of 5% MeOH-CH2Cl2 to give the pure acetophenone 6.
Example 9 7 1- [3,4-Dimethoxy-2- (2-morpholin-4-yl-ethoxy) phenyl-3-dimethylamino-propenyone (7): In one vial, 0.95 g of 5 was treated with 2 mL (excess) of dimethylformamide dimethyl acetal. The reaction was heated to 100 ° C overnight. The reaction was concentrated for an oil and a P03 / 125-VPI flash chromatography on a column of silica gel with an eluent of 5% MeOH / CH2Cl2 to give 0.57 g (51%) of enaminone 7. (4- [3,4-Dimethoxy-2- (2-morpholin-4-yl-ethoxy) phenyl-pyrimidin-2-yl) - (3-phenoxyphenyl) -amine (11-21): In a glass tube thick walled and threaded cap, 50 mg of enaminone 7 was combined with 3-phenoxyguanidine and 2 mL of acetonitrile. The reaction tube was sealed and heated at 100 ° C for two days. The solvent was evaporated in vacuo and the remaining material was recrystallized from diethyl ether / hexane to give pure 11-21 as a white solid. ^ H-NMR (CDC13, 500 MHz) d 8.32 (d, 1H), 7.62 (d, 1H), 7.60 (s, 1H), 7.48 (d, 1H), 7.32-7.22 (m, 5H), 7.19 ( s, 1H), 7.09-7.05 (m, 2H), 6.69-6.63 (m, 2H), 4.05 (t, 2H), 3.94 (s, 3H), 3.91 (s, P03 / 125-VPI 3H), 3.68 (t, 4?), 2.62 (t, 2?), 2.42 (br s, 4H).
Example 11 8 1- (5-Methoxy-2,3-dihydro-l, 4-benzodioxin-6-yl) ethan-l-one (8): In a round bottom flask, 500 mg of 1- (5-hydroxy-2,3-dihydro-1,4-benzodioxin-6-yl) ethan-1-one was dissolved in 1 mL of DMF. To this solution were added 414 mg of ¾C03 and methyl iodide (1 mL, excess). The reaction was heated at 80 ° C overnight. The reaction was poured into water and extracted with diethyl ether. The organic extract was washed with saline, dried (Na2SO4), filtered and concentrated to give 0.38 g (70%) of acetophenone £ 3.
P03 / 125-VPI Example 12 9 3-Dimethylamino-l- (5-methoxy-2,3-dihydro-benzo [1,4] dioxin-6-yl) -propenone (9): In a flask, 0.38 g (1.8 mmol) of 8 was dissolved in 1 mL of acetonitrile. Dimethylformamide dimethyl acetal (321 mg, 2.7 mmol). The bottle was sealed and heated to 90 ° C throughout the night. The reaction mixture was poured directly onto the silica gel column, which was then diluted with 70% ethyl acetate / hexane. Evaporation of the appropriate fractions gave 0.30 g (61%) of the pure 9-enaminone.
Example 13 11-17 P03 / 125-VPI [4- (5-Methoxy-2, 3-dihydro-benzo [1,4] dioxin-6-yl) -pyrimidin-2-yl] - (3-phenoxyphenyl) -amine (11-17 ): In a small vial, enaminone 9 was dissolved in 2 mL of acetonitrile. An excess of 3-phenoxyphenyl guanidine was added, the flask was sealed and the mixture was heated to reflux overnight. The reaction mixture was poured directly onto a column of silica gel, which was then eluted with 50% ethyl acetate / hexane. The appropriate fractions were combined and evaporated in vacuo to give crude pyrimidine 11-17. The pyrimidine was recrystallized from diethyl ether / hexane to give pure 11-17. "" "H-MR (CDC13, 500 MHz) d 9.78 (s, 1H), 8.45 (d, 1H), 7.75 (s, 1H), 7.48 (d, 1H), 7.35 (m, 2H), 7.23 (s) m, 3H), 7.08 (t, 1H), 6.96 (d, 2H), 6.62 (d, 1H), 6.52 (d, 1H), 4.30 (s, 4H), 3.70 (s, 3H).
Example 14 10 8-Methoxy-2,3-dihydro-benzo [1,4] dioxin-6 -carbaldehyde (10) 0.5 g (3.0 mmol) of 3,4- P03 / 125-VPI di idroxi-5-methoxybenzaldehyde, 414 mg (3.0 mmol) of K2C03 [SIC] and 3 oiL of anhydrous DMF. To this mixture 0.56 g (3.0 mmol) of 1,2-dibromoethane was added dropwise. The bottle was sealed and heated to 100 ° C throughout the night. Water was added to the reaction and the mixture was extracted with diethyl ether. The organic extract was washed with saline, dried (Na 2 SO), filtered and concentrated to give the crude product. The material was purified by silica gel chromatography using 50% ethyl acetate / hexane as the eluent to give 0.25 g (43%) of the pure 10_ aldehyde.
Example 15 1- (8-Methoxy-2,3-dihydro-benzo [1,4] dioxin-6-yl) -ethanol (11): In a 250 mL round bottom flask, 0.60 g (3.1 mmol) of 10 was dissolved in 15 mL of anhydrous tetrahydrofuran. The solution was cooled to 0 ° C and treated with 1.1 mL (3.3 mmol) of 3 M methyl magnesium chloride in THF. The reaction was stirred for a few minutes then cooled with a solution P03 / 125-VPI of 1N HCl. The mixture was extracted with ethyl acetate. The organic extract was washed with saline, dried (Na 2 SO 4), filtered and evaporated in vacuo to give alcohol 11.
Example 16 12 1- (8-Methoxy-2,3-dihydro-benzo [1,4] dioxin-6-yl) -ethanone (12): In a round bottom flask, 0.65 g (3.1 mmol) of alcohol 11 was dissolved in dichloromethane. To this solution was added an excess of manganese oxide. The suspension was heated to reflux overnight. The mixture was cooled and filtered through Celite. The filtrate was evaporated in vacuo to give 0.61 g (85%) of 12 as a yellow oil.
P03 / 125-VPI Example 17 13 3-Dimethylamino-l- (8-methoxy-2,3-dihydro-benzo [1/4] dioxin-6-yl) -propenone (13_): In one bottle, 548 g (2.6 mmol) of 12 with 2 were combined mL of dimethylformamide dimethyl acetal. The bottle was sealed and heated to 100 ° C throughout the night. The reaction was concentrated to dryness and the crude product was recrystallized from ethyl acetate / hexane to give 0.5 g (73%) of pure enaminone 13.
Example 18 1-77 P03 / 125-VPI [4- (8-Methoxy-2,3-dihydro-benzo [1,4] dioxin-6-yl) -pyrimidin-2-yl] - (3-chlorophenyl) -amine (1-77) ): In a bottle, 0.45 g (0.170 mmol) of enaminone 13 was combined with 40 mg (excess) of 3-chlorophenyl guanidine. Acetonitrile (1 mL) was added and the mixture was heated at 100 ° C overnight. The reaction was diluted with water and extracted with dichloromethane. The organic extract was dried (Na2SO4) and concentrated. The concentrated solution was poured directly onto a column of silica gel, which was eluted with 50% ethyl acetate / hexane. The appropriate fractions were combined and evaporated in vacuo to give pure pyrimidine 1-77. "" "H-NMR (CDC13, 500 MHz) d 8.42 (m, 1H), 8.13 (s, 1H), 7.48 (s, 1H), 7.32-7.20 (m, 5H), 7.10 (m, 1H), 7.0 (d, 1H), 4.49 (m, 2H), 4.30 (m, 2H), 4.03 (s, 3H).
Example 19 14 1- [3,5-Dimefcoxy-4 - (2-morpholin-4-yl-ethoxy) -phenyl) ethanone (14): 500 mg (2.5 mmol) of 5'-dimethoxy-4 'were combined in one bottle. -hydroxyacetophenone with 4-hydrochloride P03 / 125-VPI chloroethyl) raorfolin (600 mg, 3.2 mmol), and powdered potassium carbonate (1.5 g, excess). Diraethylformamide (2 mL) was added, the flask was sealed and the reaction was heated at 80 ° C overnight. The reaction was diluted with water and extracted with diethylether. The organic extract was washed with saline, dried (Na2SO4) and evaporated in vacuo to give 540 mg (67%) of 14 as a white solid.
Example 20 1- [3,5-Dimethoxy-4- (2-morpholin-4-yl-ethoxy) -phenyl] -3-dimethylamino-propenyone (15): 540 mg (1.7 mmol) of 14 with 2 were combined in a bottle. mL (excess) of dimethylformamide dimethylacetal. The reaction was sealed and heated to 130 ° C overnight. The reaction was concentrated to dryness and the residue was triturated with diethylether / hexane to give the pure enaminone.
P03 / 125-VPI Example 21 1-39 (3-Chlorophenyl) - (4 [3,5-dimethoxy-4- (2-morpholin-4-yl-efcoxy) phenyl] pyrimidin-2-yl) -amine (1-39): In a bottle, they were combined 60 mg of 3-chlorophenyl guanidone with 40 mg of 15. Acetonitrile (0.25 mL) was added, the bottle was sealed and the reaction was heated at 80 ° C for three days. The reaction was diluted with ethyl acetate and washed with saline. The organic phase was separated, dried (Na 2 SO) and evaporated in vacuo. The crude product was purified by flash chromatography on silica gel using 50% ethyl acetate / methylene chloride as eluent to give pure 1-39. "" "H-NMR (CDC13, 500 MHz) d 8.48 (d, 1H), 8.22 (s, 1H), 7.38 (s, 2H), 7.25-7.16 (m, 4H), 7.00 (d, 1H), 4.18 (br s, 2H), 3.98 (s, 6H), 3.77 (br s, 2H), 2.80 (br s, 2H), 2.59 (br s, 2H).
P03 / 125-VPI 3- (3, 4, 5- Trimethoxyphenyl) -but-2-enonitrile (16): To a slurry of 60% NaH (1.46 g, 61.1 mmol) in THF at 0 ° C was added 10.0 g ( 56.4 mmol) of ethyl phosphate (cyanomethyl). A solution of 9.88 g (47.0 mmol) of 3,4,5-trimethoxyacetophenone in THF was precipitated by adding a yellow solid. The mixture was stirred at room temperature for 30 minutes, cooled with water and extracted with ethyl acetate. The organic extract was washed with saline, dried (MgSO 4) and evaporated in vacuo to give 9.32 g (85%) of 16 as a yellow oil.
Example 23 17 P03 / 125-VPI 3- (3,4,5) -Trimethoxyphenyl) -4- (trimethylsilanyl) -but-2-enonitrile (17): To a solution of 16. (3.82 g, 16.3 mmol) in THF was He added chlorotrimethylsilane (19.6 mL, 49.17 mmol). To this solution was added a solution of lithium hexamethyldisilazide in THF (24.6 mL of 1.0M, 24.6 mmol). The solution was stirred for 1 hour, cooled with water and extracted with dichloromethane. The organic extract was dried (MgSO) and evaporated in vacuo to give a yellow oil. The oil was purified by column chromatography on silica gel using an eluent of 10-15% ethyl acetate / hexane to give 2.6 g (52%) of 17 as a white solid.
Example 24 5-Dimethylamino-3- (3,4,5-trimethoxyphenyl) penta-2,4-dienonitrile (18): To a solution of 17 (5.8 g, 19.01 mmol) in 30 mL of toluene was added 30 mL (excess ) of dimethylformamide dimethylacetal. The watery paste was heated to reflux overnight. The mixture was cooled to P03 / 125-VPI at room temperature and extracted with dichloromethane. The organic extract was washed with saline, dried (MgSO 4) and evaporated in vacuo to give a yellow oil. The oil was purified using column chromatography on silica gel using an eluent of 20-30% ethyl acetate / hexane to give 3.6 g (83%) of 18 as a yellow oil.
Example 25 2 - . 2-Bromo-4- (3,4,5-trimethoxyphenyl) pyridine (19): The gaseous HBr was bubbled into a solution of 18 (3.6 g, 16.1 mmol) in chloroform for 15 minutes. The reaction was diluted with dichloromethane, washed with water, washed with saline, dried (MgSO4) and evaporated in vacuo to give 3.2 g (62%) of 19 as an off-white solid.
P03 / 125-VPI Example 26 1-146 (3-Chlorophenyl) - [4- (3,4,5-trimethoxyphenyl) -pyridin-2-yl] -amine (1-146): To a solution of 19 (50 mg) in 3 mL of DMF was added 2 equivalents of aniline, 2 equivalents of NaH and Pd (PPh3) 4. The mixture was heated at 80 ° C overnight, cooled, poured into water and extracted with ethyl acetate. The organic extract was washed with saline, dried (Na2SO4) and evaporated in vacuo to give a brown oil. The oil was purified by preparative HPLC to give pure 1-146. Expected Mass = 370.1084; Mass Found (M + l) = 371.0. Retention time = 3.25 minutes. We have prepared other compounds of the formula I by methods substantially similar to those described in the aforementioned Examples 1-26 and those illustrated in Schemes I-IV. The characterization data for these compounds is summarized in the P03 / 125-VPI following Table 4 and includes LC / MS (observed), HPLC, and 1H NMR information. As used herein in the following Table 4, "Y" designates that the indicated data are available and found to be consistent with the structure. The numbers of the compound correspond to the numbers of the compound listed in Tables 1, 2 and 3. The term "Rt" refers to the retention time, in minutes, associated with the compound.
Table . Representation information for selected compounds PQ3 / 125-VPI Compound No. M + l (obs) ¾ NMR Rt 1-45 AND Y AND 1-46 and Y Y 1-47? And Y 1-48 AND Y Y 1-49 AND AND Y 1-50 AND Y Y 1-51 AND Y Y 1-52 AND Y Y 1-53 AND Y Y 1-54 And And Y 1-55 AND Y Y 1-56 Y - Y 1-57 Y - Y 1-58 Y - Y 1-59 Y - Y 1-60 Y - Y 1-61 Y - Y 1-62 Y - Y 1-63 Y - Y 1-64 Y - Y 1-65 Y - Y 1-66 Y - Y 1-67 Y - Y 1-68 Y - Y 1-69 Y - Y 1-70 Y - Y 1-71 Y - Y 1-72 Y - Y 1-73 Y - Y 1-74 AND Y Y 1-75 And And Y P03 / 125-VPI Compound No. M + l (obs) 2H NMR Rt 1-76 AND AND Y 1-77 AND AND Y 1-78 AND AND Y 1-79 AND AND Y 1-80 AND Y Y 1-81 AND Y Y 1-82 AND Y Y 1-83 AND Y Y 1-84 AND Y Y 1-85 And And Y 1-86 AND Y Y 1-87 AND Y Y 1-88 AND Y Y 1-89 AND Y Y 1-144 Y - Y 1-145 Y - Y 1-146 Y - Y 1-147 Y - Y 1-148 Y - Y 1-149 Y - Y 1-150 Y - Y 1-151 Y - Y 1-152 Y - Y 1-153 Y - Y 1-154 Y - Y 1-155 Y - Y 1-156 Y - Y 1-157 Y - Y 1-158 Y - Y 1-159 Y - Y 1-160 Y - Y P03 / 125-VPI Compound No. M + l (obs) H NMR Rt II -1 - - Y II- 2 - - Y II-3 - - Y II-4 - - Y II-5 - - Y II-6 - - Y II-7 - - Y II-8 - - Y II-9 - - Y 11-10 - - Y 11-11 - - Y 11-12 - - Y 11-13 - - Y 11-14 And And Y 11-15 AND Y AND 11-16 AND Y AND 11-17 AND Y Y 11-18 AND Y AND 11-19 AND Y Y 11-20 AND AND Y 11-21 AND Y AND 11-22 And And Y 11-23 Y - Y 11-24 Y - Y 11-25 Y - Y 11-44 Y - Y 11-45 Y - Y 11-46 Y - Y 11-47 Y - Y 11-48 Y - Y 11-49 Y - Y P03 / 125-VPI Compound No. M + l (obs) 2ff NMR Rt 11-50 Y - Y 11-51 Y - Y 11-52 Y - Y 11-53 Y - Y 11-54 Y - Y 11-55 Y - Y 11-57 Y - Y 11-58 Y - Y 11-59 Y - Y 11-60 Y - Y 11-61 Y - Y 11-64 Y - Y 11-65 Y - Y 11-66 Y - Y 11-67 Y - Y 11-68 Y - Y 11-69 Y - Y The following examples demonstrate how the compounds of this invention can be tested as inhibitors of the J K3, Src, Lck, GS3 and CDK2 kinases.
Example 27 Cloning, expression and purification of J K3 protein A BLAST search of the EST database using the published J K3 l cDNA, identified an EST clone (# 632588) containing the complete code sequence for the Human JNK3otl. The reactions P03 / 12S-Polymerase Chain VPI (PCR) using pfu polymerase (Strategena) were used to introduce restriction sites within the cDNA for cloning into the expression vector pET-15B in the Ncol and BamHI sites. The protein was expressed in E. coli. Due to the poor solubility of the expressed full length protein (Met 1-Gln 422), a truncated N-terminal protein was produced starting at the Ser residue at position 40 (Ser 40). This truncation corresponds to Ser 2 of the JNK1 and JNK2 proteins and is preceded by a methionine (initiation) and a glycine residue. The glycine residue was added in order to introduce an Ncol site to be cloned into the expression vector. In addition, systematic C-terminal truncations were performed by PCR to identify a construct that produces crystals with diffraction quality. One of the constructs encodes the amino acid residues Ser40-Glu402 from üTTKal and is preceded by the Met and Gly residues. The construct was prepared by PCR using deoxyoligonucleotides: 5 'GCTCTAGAGCTCCA GGGCAGCAAAAGCAAAGTTGACAA 3' (forward primer with underlined start codon) (SEQ ID NO: 1) and 5 'TAGCGGATCCTCATTCTGAATTCATTACTTCCTTGTA 3' (reverse primer with underlined downstream codon) (SEQ ID NO: 2) as primers and confirmed by the DNA sequence. The P03 / 125-VPI control experiments indicate that the truncated NK3 protein had equivalent kinase activity with respect to the myelin basic protein when activated in vi tro with an MKK7 kinase in the 51st direction. The BL21 strain of E. coli ( DE3) (Novagen) was transformed with the expression construct J 3 and cultured at 30 ° C in LB supplemented with 100 μg / ml carbenicillin in shaken flasks until the cells were in the logarithmic phase (OD60o ~ 0.8). Isopropylthio-p-D-galactosidase (IPTG) was added to a final concentration of 0.8 mM and the cells were harvested after 2 hours by centrifugation. The E. coli cell paste containing JNK3 was resuspended in 10 volumes / g lysis buffer (50 mM HEPES, pH 7.2 containing 10% glycerol (v / v), 100 M NaCl, 2 mM DTT, 0.1 mM PMSF , 2 / zg / ml Pepstatin, 1xg / ml each of E-64 and Leupeptin). The cells were lysed by the lysines on ice using a microfluidizer and centrifuged at 100,000 x < and for 30 minutes at 4 ° C. The 100,000 xgr supernatant was diluted 1: 5 with Buffer A (20 mM HEPES, pH 7.0, 10% glycerol (v / v), 2 mM DTT) and purified by cation exchange chromatography on SP-Sepharose (Pharmacia) ( column dimensions: 2.6 x 20 cm) at 4 ° C. The resin was washed with 5 column volumes of Shock Absorber A, followed by 5 column volumes of P03 / 125-VPI Shock absorber A containing 50 mM NaCl. The bound K3 J was eluted with a linear gradient of a column volume of 7.5 of 50-300 mM NaCl. JNK3 was eluted between 150-200 mM NaCl.
Example 28 Activation of JNK3 5 mg of JNK3 were diluted to 0.5 mg / ml in 50 mM HEPES buffer, pH 7.5, containing 100 mM NaCl, 5 mM DTT, 20 mM MgCl2 and 1 mM ATP. GST-MKK7 (DD) was added in a molar ratio of 1: 2.5 GST-MKK7: JT \ TK3. After incubation for 30 minutes at 25 ° C, the reaction mixture was concentrated in 5 parts by means of ultrafiltration in a Centiprep-30 (Amicon, Beverly, MA), diluted to 10 ml and added an additional 1 mM ATP. This procedure was repeated three times to remove ADP and replenish ATP. The final ATP addition was 5 mM and the mixture was incubated overnight at 4 ° C. Activated JNK3 / GST-MKK7 (DD) reaction mixture was exchanged in buffer at 50 mM HEPES, pH 7.5, containing 5 mM DTT and 5% glycerol (w / v) by dialysis or ultrafiltration. The reaction mixture was adjusted with 1.1 M potassium phosphate, pH 7.5, and purified by hydrophobic interaction chromatography (at 25 ° C) using a Rainin Hydropore column. The GST-MKK7 and the JNK3 P03 / 125-inactivated VPI does not bind under these conditions, so that a gradient of potassium phosphate of 1.1 to 0.05 M develops over 60 minutes at a flow rate of 1 ml / minute, the JNK3 is separated double phosphorylated phosphorylated JNK. Activated (ie, double phosphorylated J K3) was stored at -70 ° C to 0.25-1 mg / ml.
EXAMPLE 29 JNK INHIBITION ASSAY Compounds for the inhibition of J K3 were tested by means of a spectrophotometric enzyme coupled assay. In this assay, a fixed concentration of JNK3 (10 mM) was incubated with various concentrations of a potential inhibitor dissolved in DMSO for 10 minutes at 30 ° C in a buffer containing 0.1 M HEPES, a buffer pH 7.5 containing 10 mM MgCl2, 2.5 mM phosphoenolpyruvate, 200 μ? of NADH, 150 xg / mL of pyruvate kinase, 50 μg / mL of lactate dehydrogenase and 200 μ? of EGF receptor peptide. The EGF receptor peptide has the sequence KRELVEPLTPSGEAPNQALLR, and is a phosphoryl acceptor in the reaction of the kinase catalyzed with JNK3. The reaction was initiated by the addition of 10 μ? of ATP and the assay plate was inserted into the plate compartment of the spectrophotometer which was maintained at 30 ° C. He P03 / 125-VPI decrease in absorbance at 340 nm was monitored as a function of time. Velocity data as a function of inhibitor concentration were adjusted with the competitive inhibition kinetic model to determine ¾. Table 5 shows the activity results of the selected compounds of this invention in the JNK inhibition assay. The numbers of the compound correspond to the numbers of the compound in Tables 1, 2 and 3. Compounds that have a ¾ less than 0.1 micromolar (μ?) Are evaluated as "A", compounds that have an ¾ between 0.1 and 1 μ? are evaluated as "B" and compounds that have a ¾ greater than 1 μ? They were rated as "C". The activity values "D", "E" and "F" correspond to the inhibition of percentage at a concentration of the inhibitor of 2 μ ?. Compounds having an activity designated "D" provided a percent inhibition less than or equal to 33%; Compounds having an activity designated "E" provided a percent inhibition of between 24% and 66%; and compounds having an activity designated "F" provided a percent inhibition of between 67% and 100%.
P03 / 125-VPI Table 5. Activity in the JNK3 inhibition assay.
P03 / 125-VPI No. Activity No. Activity No. Activity 1-88 B 1-89 B 1-94 A 1-146 B 1-147 B 1-151 B 1-154 B 1-155 B 11-32 A 11-33 C - - - - EXAMPLE 30 Src Inhibition Assay The compounds were tested for their inhibitory activity on full-length recombinant human Src kinase (ü state Biotechnology, cat. do not. 14-117) expressed and purified from the viral cells of the staff. The activity of Src kinase was monitored following the incorporation of 33P of ATP into the tyrosine of a substrate of the poly Glu-Tyr random polymer composition, Glu: Tyr = 4: 1 (Sigma, cat.No.P-0275) . The following were final concentrations of the test components: 0.05 M HEPES, pH 7.6, 10 mM MgCl2, 2 mM DTT, 0.25 mg / ml BSA, 10 μM. ATP (1-2 μl 33 P-ATP per reaction), 5 mg / ml poly Glu-Tyr, and 1-2 units of recombinant human Src kinase. In a typical assay, all components of the reactions with the exception of ATP were pre-mixed and aliquots were deposited within the receptacles of the assay plate. The inhibitors dissolved in DMSO were added to the receptacles to give a final DMSO concentration of 2.5%. The test plate P03 / 125-VPI was incubated at 30 ° C for 10 minutes before starting the reaction with 33P-ATP. After 20 minutes of the reaction, the reactions were stopped with 150 μ? of 10% trichloroacetic acid (TCA) containing 20 mM Na3P04. The samples of the stopped reaction were then transferred to a 96-well filter plate (Whatrnan, U I-Filter GF / F Glass Fiber Filter, Cat No. 7700-3310) installed in a vacuum distributor of filter plate. The filter plates were washed four times with 10% TCA containing 20 M Na3P04 and then four times with methanol. Then, 200 μ? Was added to each receptacle? scintillation fluid. The plates were sealed and the amount of radioactivity associated with the filters was quantified in a TopCount scintillation counter. Table 6 shows the activity results of the selected compounds of this invention in the SRC inhibition assay. The compound numbers correspond to the compound numbers in Tables 1, 2 and 3 · Compounds that have a ¾_ less than 0.1 micromolar (μ?) Are rated "A", the compounds that have a ¾. between 0.1 and 1 μ? are evaluated as "B" and compounds that have a ¾ greater than 1 μ? They were rated as "C". The values of activity "D", "E" and "F" correspond to the percentage inhibition at an inhibitor concentration P03 / 125-VPI of 2 jLtM, Compounds having an activity designated as "D" provided a percentage of inhibition less than or equal to 33%; Compounds having an activity designated "E" provided a percent inhibition of between 24% and 66%; and compounds having an activity designated "F" provided a percent inhibition of between 67% and 100%.
Table 6. Activity in the SRC inhibition assay.
Example 31 Assay of inhibition of Lck compounds were tested for their inhibitory activity on purified LK kinase from bovine thymus (Upstate Biotechnology, cat # 14-106). The activity of Lck kinase was monitored by following the incorporation of 33P of ATP into the tyrosine of a substrate of random poly Glu-Tyr polymer composition, Glu: Tyr = 4: 1 (Sigma, cat.No.P-0275 ). The following were the final concentrations of the test components: 0.05 M HEPES, pH 7.6, 10 mM MgCl2, 2 mM DTT, 0.25 mg / ml BSA, 10? ATP (1-2 μ ?? 33P-ATP per reaction), 5 mg / ml poly Glu-Tyr and 1-2 units of Lck kinase. In a typical assay, all components of the reactions, with the exception of ATP, were pre-mixed and aliquots were deposited into the receptacles of the assay plate. The inhibitors dissolved in DMSO were added to the receptacles to give a final DMSO concentration of 2.5%. The assay plate was incubated at 30 ° C for 10 minutes before starting the reaction with 33P-ATP. After 20 minutes of the reaction, the reactions were stopped with 150 μ? of 10% trichloroacetic acid (TCA) containing 20 mM Na3P04. The stopped reaction samples were then transferred to a filter plate (Whatman, U I-Filter GF / F Glass Fiber Filter, cat No. 7700-3310) installed in a vacuum distributor of filter plate. The filter plates were washed four times with 10% TCA containing 20 mM Na3P0 and then P03 / 125-VPI four times with methanol. Then, 200 μ? Was added to each receptacle? scintillation fluid. The plates were sealed and the amount of radioactivity associated with the filters was quantified in a TopCount scintillation counter. Table 7 shows the activity results of the selected compounds of this invention in the Lck inhibition assay. Compound numbers correspond to the compound numbers in Tables 1, 2 and 3. Compounds that have a K¿ of less than 0.1 micromolar (μ?) Are scored as "A", compounds that have a K ± between 0.1 and 1 μ? are evaluated as "B" and compounds that have a ¾ greater than 1 μ? They are valued as "C". The values of activity "D", "E" and "F" correspond to the inhibition of percentage at a concentration of the inhibitor of 5 μ ?. Compounds having an activity designated "D" provided a percentage of inhibition less than or equal to 33%; Compounds having an activity designated "E" provided a percent inhibition of between 24% and 66%; and compounds having an activity designated "F" provided a percent inhibition of between 67% and 100%.
P03 / 125-VPI Table 7. Activity in the Lck inhibition test.
P03 / 125-VPI Example 32 GSK-3 Inhibition Assay The compounds were classified as follows by their ability to inhibit Glycogen Synthase Kinase 3 (GSK-3) by a standard coupled enzyme assay (Fox et al. (1998). Protein Sci 7, 2249). To a stock solution of assay buffer containing 0.1M HEPES 7.5, 10 M MgCl2, 25 mM NaCl, 2.5 mM phosphoenolpyruvate, 300 μ? NADH, 1 mM DTT, 30 μg / mL kinase pyruvate (HSSPHQ -SEDEEE, American Peptide, Sunnyvale, CA) and 60 nM GSK-3, a solution of 30 μ? of the compound in DMSO and the resulting mixture was incubated at 30 ° C for 5 minutes. The reaction was initiated by the addition of 10 μ? ATP. Reaction values were obtained by monitoring the absorbance at 340 nM over a 5 minute reading time at 30 ° C using a plate reader from Molecular Devices (Sunnyvale, CA). The IC5o was determined from the velocity data, as a function of the concentration of the inhibitor. Table 8 shows the activity results of the selected compounds of this invention in the GSK-3 inhibition assay. The compound numbers correspond to the compound numbers in Tables 1, 2 and 3. Compounds that have a ¾ less than 0.1 micromolar (μ?) Are evaluated as "A", the compounds that have a K ± P03 / 125-VPI between 0.1 and 1 μ? are evaluated as "B" and compounds that have a K¿ greater than 1 μ? They are valued as "C".
Table 8. Inhibitory activity of GSK-3 with the selected compounds P03 / 125-VPI Example 33 CDK2 inhibition assay The compounds were presented in the following manner for their ability to inhibit CDK2 using a standard coupled enzyme assay (Fox et al (1998) Protein Sci 7, 2249). For a stock solution of assay buffer containing 0.1M HEPES 7.5, 10mM MgCl2, 1mM DTT, 25mM NaCl, 2.5mM phosphoenolpyruvate, 300mM NADH, 30mg / ml pyruvate kinase, 10mg / ml lactate dehydrogenase , 100 mM ATP and a peptide of 100 μ? (MAHHHRSPRKRAKKK, American Peptide, Sunnyvale, CA) was added to a DMSO solution of a compound of the present invention for a final concentration of 30 μ ?. The resulting mixture was incubated at 30 ° C for 10 minutes. The reaction was initiated by the addition of 10 L of the stock solution of CDK-2 / Cyclin A to give a final concentration of 25 nM in the assay. The reaction values were obtained by monitoring the absorbance at 340 nm over a 5 minute reading time at 30 ° C using a BioRad Ultramark plate reader (Hercules, CA). The K¿ values were determined by the velocity data as a function of the inhibitor concentration. Table 9 shows the results of the activity of the selected compounds of this invention in the P03 / 125-VPI inhibition assay of CDK2. The compound numbers correspond to the compound numbers in Tables 1, 2 and 3. The compounds that have a ?? less than 2 micromolar (μ?) are evaluated as "A", the compounds that have a K¿ between 2 and 5 μ? they are valued as "B" and the compounds that have a ¾. greater than 5 jiM are valued as "C".
Table 9. Inhibitory activity of CDK2 with the selected compounds P03 / 125-VPI No. Activity No. Activity No. Activity 11-51 C 11-52 C 11-53 C 11-54 C 11-55 C 11-56 C 11-57 c 11-58 c 11-59 c 11-60 c 11-61 c 11-62 c 11-70 c 11-71 c 11-72 c 11-73 c 11-74 c 11-75 c 11-76 c While we have described various embodiments of this invention, it will be apparent that our basic examples may be altered to provide other embodiments utilizing the compounds and methods of this invention. Therefore, it will be appreciated that the scope of this invention will be defined by the appended claims and not by the specific modalities that have been represented by way of example.
P03 / 125-VPI

Claims (1)

  1. CLAIMS; A compound of formula I or II or a pharmaceutically acceptable derivative thereof, wherein: each W is independently selected from nitrogen or CH; each R1, R2 and R3 is independently selected from halogen, QR, Q (n) CN, Q (n) N02 or Q (n) Ar2; wherein: R1 and R2 or R2 and R3 are optionally taken together to form a 4-8 membered saturated, partially unsaturated, or completely unsaturated ring, having 0-3 heteroatoms independently selected from nitrogen, oxygen or sulfur; n is zero or one; Q is an alkylidene chain of < ¾-4, wherein the methylene unit of Q is optionally substituted by O, S, NR, NRCO, NRCONR, NRC02, CO, C02, CONR, 0C (O) R, S02, P03 / 125-VPI S02NR, NRS02, NRS02NR, C (0) C (0) or C (0) CH2C (0); each R is independently selected from hydrogen or an optionally substituted 1.-C4 aliphatic group, wherein: two R's attached to the same nitrogen atom are optionally taken together with the nitrogen atom to form a 3-7 membered ring saturated, partially unsaturated, or completely unsaturated, having 1-2 additional heteroatoms independently selected from nitrogen, oxygen or sulfur; R4 is Ar1, T-Ar2 or T (n) -Ar3; T is an alkylidene chain of Ci_2, wherein a methylene unit of T is optionally replaced by O, R, NRCO, NRCONR, NRC02, CO, C02, CO R, 0C (0) NR, S02, S02NR, NRS02, NRS02NR , C (0) C (0) OC (O) C¾C (O); Ar1 is a 5-6 membered monocyclic or 8-10 membered bicyclic ring system, saturated, partially unsaturated, or completely unsaturated; wherein: Ar1 is optionally substituted with up to five substituents, wherein the first substituent is selected from Rx or R5, and wherein the additional substituents are independently selected from R5; each Rx is independently selected from a 5-6 member aryl ring, which has 0-3 P03 / 125-VPI heteroatoms selected from nitrogen, oxygen or sulfur, wherein: Rx is optionally substituted with 1-3 Rs; each R5 is independently selected from R, halogen, N02, CN, OR, SR, N (R) 2, NRC (0) R, NRC (0) JST (R) 2, RC02R, C (0) R, C02R, C (0) N (R) 2, 0C (0) N (R), SOR, S02R, S02N (R) 2, N S02R, NRS02N (R) 2, C (0) C (0) ROC ( O) CH2C (O) R; Ar2 is a 5-6 membered monocyclic ring, saturated, partially unsaturated, or completely unsaturated, having 0-3 heteroatoms independently selected from nitrogen, oxygen or sulfur, or an 8-10 membered bicyclic ring system, saturated, partially unsaturated, or completely unsaturated, having 0-5 heteroatoms independently selected from nitrogen, oxygen or sulfur; wherein: Ar2 is optionally substituted with up to five substituents, wherein the first substituent is selected from Rx or R5, and wherein any additional substituents are independently selected from R5; Ar3 is a 6-membered aryl ring, having 0-2 nitrogens, wherein: Ar3 is substituted with a group Z-R6 and is optionally substituted with 1-3 R5; Z is a Ci-C3 alkylidene chain, where up to two non-adjacent methylene units of Z, are P03 / 125-VPI optionally replaced by CO, C02, COCO, CONR, OCONR, RNR, NRNRCO, NRCO, NRC02, NRCONR, SO, S02, NRS02, S02NR, NRS02NR, O, S or NR; and R6 is selected from Ar2, R, halogen, N02, CN, OR, SR, N (R) 2, RC (0) R, NRC (0) N (R) 2, NRC02R, C (0) R, C02R , OC (0) R, C (0) N (R) 2, OC (0) N (R) 2, SOR, S02R, S02N (R) 2, NRS02R, NRS02N (R) 2, C (0) C (0) R or C (0) CH2C (0) R; with the proviso that: (i) when R4 is phenyl substituted with two ORs, where R is not hydrogen, the two ORs occupy different positions on the phenyl ring of simultaneously meta and para and (ii) the compound is different from a compound of formula III wherein: A is a phenyl ring substituted with one more groups selected from halogen, CN, 0C (0) NH2, C02R "COR10, S02N (R10) 2, N (R10) 2, OR10, or fluoroalkyl, in where P03 / 125-VPI each R10 is independently selected from hydrogen or a C1-C7 alkyl group, optionally substituted with NH2 / H (Ca-C7 alkyl) or (Ci-C7 alkyl) 2; and B is selected from halogen, CN, OC (0) NH2, C02R10, COR10, SO2N (R10) 2, N (R10) 2, OR10 or fluoro- (Ca-C7 alkyl). 2. The compound according to claim 1, wherein: R1, R2 and R3 are selected from halogen, QR or QAr2; Q is an alkylidene chain of (¾_3 wherein a methylene unit of Q is optionally replaced by -O-, -S-, -NHCO- or -NR-; and Ar2 is an optionally substituted 5-6 membered, saturated ring , partially unsaturated, or completely unsaturated, having 0-2 heteroatoms, independently selected from nitrogen, oxygen or sulfur 3. The compound according to claim 2, wherein: R1, R2 and R3 are independently selected from OH, OCH3, OCH2CH3, NHCOMe, H2, NH (aliphatic group of C3.-4), N (aliphatic group of Ci_4) 2, O (CH2) 2morpholin-4-yl, 0 (C¾) 2NH2, O (C¾) 2MH (aliphatic group of C1?), O (C¾) 2N (aliphatic group of? _ 4) 2, bromine, chlorine or fluoro; or R1 and R2 or R2 and R3 are taken together to form P03 / 125-VPI and Ar2 more preferred are morpholin-4-yl, pyrrolidin-1-yl, piperidin-1-yl, thiomorpholin-4-yl; pyrazol-1-yl or imidazol-1-yl. 4. The compound according to claim 1, wherein: R4 is selected from: (a) a 6-membered, saturated, partially unsaturated ring or an aryl having 0-3 nitrogens; (b) a 9-10 member bicyclic aryl ring having 0-2 nitrogens; or (c) a 5-membered heteroaryl ring having 2-3 heteroatoms independently selected from nitrogen, oxygen or sulfur. 5. The compound according to claim 4, wherein the ring is substituted with 1-3 groups independently selected from Rx, R, halogen, N02, OR, N (R) 2 or Z-R6. 6. The compound according to claim 5, wherein Rx is selected from a phenyl, pyridyl or P03 / 125-VPI pyrimidinyl optionally substituted with 1-2 R5. The compound according to claim 5, wherein Z is an alkylidene chain of Ci_, wherein a methylene unit of Z is optionally replaced by -0-, -S-, -S02- or -NH-. The compound according to claim 4, wherein the ring is selected from a substituted ring of phenyl, cyclohexyl, naphthyl, pyridyl, pyrimidinyl, triazinyl, thiazolyl, thiadiazolyl, pyrazolyl, isoxazolyl, indazolyl or benzimidazolyl. The compound according to claim 8, wherein the ring is optionally substituted with 1-2 groups which are independently selected from chloro, fluoro, bromo, methyl, ethyl, t-butyl, isopropyl, cyclopropyl, nitro, OMe, OEt, CF3, N¾, benzyl, benzyloxy, OH, methylenedioxy, S02NH2, phenoxy, O-pyridinyl, S02phenyl, nitrophenoxy, aminophenoxy, S-dimethylpyrimidine, NH-phenyl, NH-methoxyphenyl, pyridinyl, aminophenyl, phenol, chloro-fluoro-phenyl, dimethylaminophenyl, CF3-phenyl, dimethylphenyl, chlorophenyl, fluorophenyl, methoxyphenoxy, chlorophenoxy, ethoxyphenoxy or fluorophenoxy. 10. A compound selected from those listed in any of Tables 1 to 3. 11. A composition comprising a compound according to any of claims 1-10 and a carrier. P03 / 125-VPI adjuvant or pharmaceutically acceptable vehicle. The composition according to claim 11, further comprising an additional therapeutic agent selected from an antiproliferative agent, an anti-inflammatory agent, an immunomodulatory agent, a neuophic factor, an agent for treating cardiovascular disease, an agent, an agent antiviral, an agent for treating blood disorders, an agent for the treatment of diabetes or an agent for treating immunodeficiency disorders. 13. A method of inhibiting the kinase activity of JNK3, GSK-3, CD2, Lck or Src in a biological sample comprising the step of contacting said biological sample with: a) a compound according to claim 1; or b) a composition according to claim 11. 14. A method for treating or decreasing the severity of a disease or condition mediated by JNK3-, GSK-3-, CDK2-, Lck- or Src- in a patient comprising the step of administering to said patient a composition according to claim 11. 15. A method for treating or decreasing the severity of a disease or condition in a patient selected from inflammatory diseases, autoimmune diseases, destructive bone disorders, P03 / 125-VPI neurodegenerative diseases, reperfusion / stroke ischemia, heart attacks, angiogenic disorders, hypoxia in organs, vascular hyperplasia, cardiac hypertrophy, platelet aggregation induced by thrombin or a condition associated with proinflammatory cytokines, comprising step of administering to said patient a composition according to claim 11. 16. A method for treating or reducing the severity of a disease or condition in a patient, selected from hypercalcemia, osteoporosis, osteoarthritis, symptomatic treatment of bone metastasis, rheumatoid arthritis , inflammatory bowel disease, multiple sclerosis, psoriasis, lupus, graft-versus-host disease, T cell-mediated hypersensitivity disease, Hashimoto's thyroiditis, Guillain-Barre syndrome, chronic obstructive pulmonary disorder, contact dermatitis, Paget's disease, asthma, ischemia or reperfusion injury, allergic disease, atopic dermatitis or allergic rhinitis, comprising the step of administering to a patient a composition according to claim 11. 17. A method for treating or decreasing the severity of a disease or condition in a patient selected from diabetes, Alzheimer's disease , Huntington and Parkinson's, dementia associated with AIDS, amyotrophic lateral sclerosis (AML) P03 / 125-VEI English), multiple sclerosis (MS), schizophrenia, cardiomycete hypertrophy or baldness, comprising the step of administering to said patient a composition according to claim 11. 18. A method for treating or decreasing the severity of a cancer comprises the step of blocking the transition of cancer cells to their proliferative phase by inhibiting CDK2 with: a) a compound according to claim 1; or b) a composition according to claim 11. 19. The method according to claim 14 comprises the additional step of administering to said patient an additional therapeutic agent selected from an antiproliferative agent, an anti-inflammatory agent, an immunomodulatory agent, a neurotrophic factor. , an agent for treating cardiovascular disease, an agent for treating liver disease, an antiviral agent, an agent for treating blood disorders, an agent for treating diabetes or an agent for treating immunodeficiency disorders, wherein: said Additional therapeutic agent is appropriate for the disease being treated; and said additional therapeutic agent is administered together with said composition as a single dose form or separately from the composition, as part of a P03 / 125-VPI multiple dose form. 20. A composition for coating an implantable device comprising a compound according to claim 1 and a suitable carrier for coating said implantable device. 21. An implantable device coated with a composition according to claim 20. P03 / 125-VPI
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